Kurs “ Allgemeine und systematische Pharmakologie und Toxikologie” WS 2017/2018

Seminarthema IV: Mediatoren Der Inhalt bzw. die Gliederung der Referate ist frühzeitig mit der/dem zuständigen Dozentin/en abzusprechen. Alle Referate sollten max. 15 Minuten dauern und den Einsatz von Hilfsmitteln (Powerpoint-Präsentation) umfassen. Bei Wiederverwendung von Präsentationen von Kolleginnen/en vorangegangener Seminare werden keine Creditpunkte (siehe Link "Creditpunkte") vergeben. Dr. Claudia Walliser (Pharmakologie/Toxikologie) N26-5201 500-65520/65508 Referat 1: H1-Antihistaminika (erster Termin)

Simons, F. Estelle R. und Simons, K. J: Histamine and H1-antihistamines: Celebrating a century of progress. J Allergy Clin Immunol (2011) 128: 1139-1150.e4

Yanai, K., Yoshikawa, T., Yanai, A., Nakamura, T., Iida, T., Leurs, R. and Tashiro, M.: The clinical pharmacology of non-sedating antihistamines. Pharmacology & Therapeutics (2017) 178: 148-156

Dittmann, A. und Mohr, K.: H1-Antihistaminika: Pharmakologische Grundlagen der Wirkung. Pharm. Unserer Zeit (2004) 2: 100-105

Haen, E.: Arzneiwechselwirkungen mit H1-Antihistaminika. Pharm. Unserer Zeit (2004) 2: 106-107

Ihr Referat sollte folgende Punkte beinhalten: Wirkungen, Einsatzmöglichkeiten und unerwünschte Wirkungen der H1-Antihistaminika der 1. und der 2. Generation mit Beispielen. Die Wirkungen, Nebenwirkungen und Kontraindikationen sollen anhand der pharmakodynamischen und pharmakokinetischen Eigenschaften dieser Substanzen diskutiert werden. Referat 2: Migräne (zweiter Termin)

Antonaci, F., Ghiotto, N., Wu, S., Pucci, E. and Costa, A.: Recent advances in migraine therapy. SpringerPlus (2016) 5:637, 1-14

Diener, H.-C.: aktuelle Leitlinie zur Therapie der Migräne (2013-2017), Deutsche Gesellschaft für Neurologie

Loder E.: Triptan therapy in migraine. N ENGL J MED (2010) 363: 63-70

In Ihrem Referat sollten Sie die akute und die prophylaktische medikamentöse Therapie der Migräne darstellen. Auf die Wirkungsmechanismen und Nebenwirkungen der Serotonin-Rezeptoragonisten (Triptane) sollten Sie genauer eingehen. Wann ist eine Migräneprophylaxe indiziert? Geben Sie eine kurze Zusammenfassung über die Möglichkeiten der Migräneprophylaxe der ersten Wahl. Die Epidemiologie, Symptome und Pathogenese der Migräne sind nicht Gegenstand ihres Referates.

Referat 3: Antileukotriene (zweiter Termin)

Scott, J. P. and Peters-Golden, M.: Antileukotriene agents for the treatment of lung disease. Am J Respir Crit Care Med (2013) 188: 538-544

Dahlen S-E.: Treatment of asthma with antileukotrienes: First line or last resort therapy? European Journal of Pharmacology (2006) 533: 40-56 + neueste Fachinfo zu Montelukast

http://www.asthma.versorgungsleitlinien.de; Montelukast in der Asthma-Stufentherapie von Erwachsenen und Kindern; siehe S. 32 + 33 in der Langfassung

In Ihrem Referat sollten Sie auf die pathophysiologischen Effekte der Leukotriene, speziell bei Asthma, eingehen. Erklären Sie die Wirkmechanismen der Antileukotriene jeweils mit Beispielen. Beschreiben Sie die Wirkungen der CysLT1-Rezeptor-Antagonisten bei der Behandlung von Asthma, die Vorteile der Kombinationstherapie und nennen Sie weitere Einsatzmöglichkeiten dieser Substanzen. Die Biosynthese und der Metabolismus der Leukotriene sind nicht Gegenstand Ihres Referats.

Clinical reviews in allergy and immunology

Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD

Histamine and H1-antihistamines: Celebrating a century ofprogress

F. Estelle R. Simons, MD, FRCPC,a and Keith J. Simons, PhDb Winnipeg, Manitoba, Canada

INFORMATION FOR CATEGORY 1 CME CREDIT

Credit can now be obtained, free for a limited time, by reading the review

articles in this issue. Please note the following instructions.

Method of Physician Participation in Learning Process: The corema-

terial for these activities can be read in this issue of the Journal or online at the

JACIWebsite:www.jacionline.org. The accompanying testsmayonlybe sub-

mitted online at www.jacionline.org. Fax or other copies will not be accepted.

Date of Original Release: December 2011. Credit may be obtained for

these courses until November 30, 2013.

Copyright Statement: Copyright � 2011-2013. All rights reserved.

Overall Purpose/Goal: To provide excellent reviews on key aspects of

allergic disease to those who research, treat, or manage allergic disease.

Target Audience: Physicians and researchers within the field of allergic

disease.

Accreditation/Provider Statements and Credit Designation: The

American Academy of Allergy, Asthma & Immunology (AAAAI) is ac-

credited by the Accreditation Council for Continuing Medical Education

(ACCME) to provide continuing medical education for physicians. The

AAAAI designates these educational activities for a maximum of 1 AMA

PRA Category 1 Credit�. Physicians should only claim credit commensu-

rate with the extent of their participation in the activity.

List of Design Committee Members: F. Estelle R. Simons, MD,

FRCPC, and Keith J. Simons, PhD

Activity Objectives

1. To understand new insights into the mechanism of action of

H1-antihistamines.

2. To know when it is appropriate to use H1-antihistamines.

3. To list the adverse effects of H1-antihistamines.

Recognition of Commercial Support: This CME activity has not re-

ceived external commercial support.

Disclosure of Significant Relationships with Relevant Commercial

Companies/Organizations: F. E. R. Simons is a member of the Uriach

medical advisory board. K. J. Simons declares that he has no relevant con-

flicts of interest.

In this review we celebrate a century of progress since the initialdescription of the physiologic and pathologic roles of histamineand 70 years of progress since the introduction ofH1-antihistamines for clinical use. We discuss histamine andclinically relevant information about the molecular mechanismsof action of H1-antihistamines as inverse agonists (notantagonists or blockers) with immunoregulatory effects. Unlikefirst (old)–generation H1-antihistamines introduced from 1942to the mid-1980s, most of the second (new)–generationH1-antihistamines introduced subsequently have beeninvestigated extensively with regard to clinical pharmacology,efficacy, and safety; moreover, they are relatively free fromadverse effects and not causally linked with fatalities afteroverdose. Important advances include improved nasal andophthalmic H1-antihistamines with rapid onset of action (inminutes) for allergic rhinitis and allergic conjunctivitistreatment, respectively, and effective and safe use of high (up to4-fold) doses of oral second-generation H1-antihistamines forchronic urticaria treatment. New H1-antihistamines introducedfor clinical use include oral formulations (bilastine and

From athe Department of Pediatrics & Child Health and the Department of Immunology,

Faculty ofMedicine, and bthe Faculty of Pharmacy and the Department of Pediatrics &

Child Health, Faculty of Medicine, University of Manitoba.

Received for publication June 9, 2011; revised September 6, 2011; accepted for publica-

tion September 7, 2011.

Available online October 27, 2011.

Corresponding author: F. Estelle R. Simons, MD, FRCPC, Room FE125, 820 Sherbrook

St, Winnipeg, R3A 1R9 Manitoba, Canada. E-mail: lmcniven@hsc.mb.ca.

0091-6749/$36.00

� 2011 American Academy of Allergy, Asthma & Immunology

doi:10.1016/j.jaci.2011.09.005

rupatadine), and ophthalmic formulations (alcaftadine andbepotastine). Clinical studies of H3-antihistamines withenhanced decongestant effects have been conducted in patientswith allergic rhinitis. Additional novel compounds being studiedinclude H4-antihistamines with anti-inflammatory effects inallergic rhinitis, atopic dermatitis, and other diseases.Antihistamines have a storied past and a promising future.(J Allergy Clin Immunol 2011;128:1139-50.)

Key words: Histamine, H1-antihistamine(s), H2-antihistamine(s),H3-antihistamine(s), H4-antihistamine(s), allergic rhinitis, allergicconjunctivitis, urticaria, atopic dermatitis, cetirizine, desloratadine,fexofenadine, levocetirizine, loratadine, rupatadine, bilastine, alcaf-tadine, bepotastine

In 2010-2011, we celebrate the centenary of the initialdescription of the physiologic and pathologic effects of histamine.In 2012, we celebrate the 70th anniversary of the introduction ofH1-antihistamines for clinical use. These and other importantevents related to histamine, histamine receptors, and H1-antihista-mines are shown in Fig 1.1-18

HISTAMINE AND HISTAMINE RECEPTORSHistamine, a structurally simple chemical messenger, is a

natural body constituent synthesized from the amino acid histi-dine by L-histidine decarboxylase, an enzyme expressed in manydifferent cell types. Histamine plays an important physiologicrole in human health, exerting its diverse effects through 4subtypes of receptors (Table I).11-18 Through the H1-receptor, it

1139

J ALLERGY CLIN IMMUNOL

DECEMBER 2011

1140 SIMONS AND SIMONS

Abbreviations used

BBB: B

lood-brain barrier

CNS: C

entral nervous system

PET: P

ositron emission tomography

contributes to regulation of cell proliferation and differentiation,hematopoiesis, embryonic development, regeneration, andwound healing and plays an important role in neurotransmissionin the central nervous system (CNS). It is produced in neuronswith cell bodies in the tuberomamillary nucleus of the posteriorhypothalamus that send their axons throughout the cerebrum,cerebellum, posterior pituitary, and spinal cord. It has anticon-vulsant activity and contributes to regulation of vigilance (alert-ness and attention), cognition, learning, memory, and thecircadian sleep-wake cycle, as well as to energy and endocrinehomeostasis.1,18-20

Through its 4 receptor subtypes, histamine plays an importantrole in a complex system of immunoregulation and in acute andchronic allergic inflammation.21 Through the H1-receptor, it in-creases antigen-presenting cell capacity, increases release ofhistamine and other mediators from mast cells and basophils,downregulates humoral immunity, and upregulates TH1 priming,TH1 proliferation, IFN-g production, cellular adhesion moleculeexpression, and chemotaxis of eosinophils and neutrophils(Table I).18

Histamine receptors are heptahelical transmembrane mole-cules that transduce extracellular signals by way of G proteins to

FIG 1. Celebrating a century of progress: timeline fe

histamine receptors, and H1-antihistamines. The phy

described in 1910-1911. H1-antihistamines were introdu

rgan (1942), diphenhydramine (1946), and chlorphenir

second (new)–generation H1-antihistamines were introd

rons were identified in the CNS. Cloning and character

for the H2-receptor in 1991, the H1-receptor in 1993, the

intracellular second messenger systems. These receptors haveconstitutive activity, defined as the ability to trigger downstreamevents, even in the absence of ligand binding. Their active andinactive states exist in equilibrium; at rest, the inactive stateisomerizes with the active state and vice versa (Fig 2).1,11-16,18,21

The low H1-receptor selectivity of first-generation H1-antihista-mines has been attributed to direct interaction with tryptophan4286,48, a highly conserved key residue in G protein–coupled re-ceptor activation.22

H1 receptor–deleted mice have neurologic abnormalities, in-cluding aggressive behavior and impaired vigilance, learning,memory, and locomotion, in addition to metabolic and immuno-logic abnormalities.18

H1-ANTIHISTAMINESMore than 45 H1-antihistamines are available worldwide, com-

prising the largest class of medications used in the treatment ofallergic diseases. New H1-antihistamines, including bilastineand rupatadine for oral administration and bepotastine and alcaf-tadine for ophthalmic application, have been introduced. Promis-ing H1-antihistamine/glucocorticoid nasal formulations are beinginvestigated.23-28

H1-antihistamines act as inverse agonists that combine withand stabilize the inactive conformation of the H1-receptor, shift-ing the equilibrium toward the inactive state. For more than 50years, they were described as H1-receptor antagonists or H1-re-ceptor blockers; however, these out-of-date terms do not accu-rately reflect their molecular mechanism of action (Fig 2).1,15-18,21

aturing historical highlights related to histamine,

siologic and pathologic effects of histamine were

ced for clinical use in the 1940s, for example, ante-

amine (1949). In the 1980s, relatively nonsedating

uced for clinical use, and histamine-containing neu-

ization of human histamine receptors was reported

H3-receptor in 1999, and the H4-receptor in 2000.1-18

TABLE I. Histamine receptor subtypes17,18

GPCR signaling* Expression Representative antihistamines Clinical use/potential usez

H1-receptor Gq/G11 family to

phospholipase

C stimulation

CNS neurons, smooth muscle cells

(vascular, respiratory, and GI),

CVS, neutrophils, eosinophils,

monocytes, macrophages, DCs,

T and B cells, endothelial cells,

epithelial cells

Chlorpheniramine,

diphenhydramine, hydroxyzine,

cetirizine, desloratadine,

fexofenadine, levocetirizine,

loratadine, and 40 others

Allergic rhinitis, allergic

conjunctivitis, urticaria; used in

many other allergic diseases and

nonallergic diseases, including

CNS diseases

H2-receptor Gs family to adenylate

cyclase stimulation

and [ cyclic AMP

Gastric parietal cells, smooth muscle,

CNS, CVS, neutrophils,

eosinophils, monocytes,

macrophages, DCs, T and B cells,

endothelial cells, epithelial cells

Cimetidine, ranitidine, famotidine,

nizatidine

Peptic ulcer disease and

gastroesophageal reflux disease

H3-receptor Gi/o family to adenylate

cyclase inhibition

and Y cyclic AMP

CNS and peripheral neurons�, CVS,lungs, monocytes, eosinophils,

endothelial cells

No agents approved for use to date;

those in clinical trials include JNJ

39220675 and PF-03654746 for

allergic rhinitis

Potentially useful in allergic rhinitis

and neurologic disorders,

including Alzheimer disease,

attention-deficit hyperactivity

disorder, schizophrenia, epilepsy,

narcolepsy, and neuropathic pain;

also in obesity

H4-receptor Gi/o family to adenylate

cyclase inhibition and

Y cyclic AMP

Neutrophils, eosinophils, monocytes,

DCs, Langerhans cells, T cells,

basophils, mast cells, fibroblasts,

bone marrow, endocrine cells, and

CNS

No agents approved for use to date;

those in clinical trials have

included JNJ 7777120 for allergic

rhinitis and pruritus, UR 65380

and UR 63825 for pruritus

Potentially useful in allergic rhinitis,

atopic dermatitis/eczema, and

asthma and in other chronic

inflammatory disorders and

autoimmune disorders

CVS, Cardiovascular system; DC, dendritic cell; GI, gastrointestinal; GPCR, G protein–coupled receptor.

*The primary signaling mechanism is shown. Additional intracellular signals at the H1-receptor include phospholipase C, 1,2-diacylglycerol, inositol 1,4,5-triphosphate,

phosphatidylinositol 4,5-biphosphate, protein kinase C, and intracellular calcium. Additional intracellular signals at the H2-receptor include protein kinase A, cyclic AMP

responsive element-binding protein, and exchange protein directly activated by cyclic AMP. At the H3- and H4-receptors, stimulation of calcium mobilization from intracellular

stores constitutes another important signal.

�The H3-receptor is a presynaptic autoreceptor on histaminergic neurons in the CNS and on non–histamine-containing neurons in the CNS and peripheral nervous system. It

regulates levels of a variety of neurotransmitters, including norepinephrine, acetylcholine, serotonin, and dopamine.

�Issues in the development of H3- and H4-antihistamines include nondisclosure of ligand structure, instability of some of the ligands that have been synthesized, different outcomes

in different species, and adverse events in some clinical trials. There is nevertheless considerable optimism that H3- and H4-antihistamines will eventually prove effective and safe

in the treatment of allergic disorders, not only in patients with allergic rhinitis but also in patients with atopic dermatitis and asthma.

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SIMONS AND SIMONS 1141

H1-antihistamines downregulate allergic inflammation di-rectly through the H1-receptor by interfering with histamine ac-tion at H1-receptors on sensory neurons and small blood vessels.Through the ubiquitous transcription factor nuclear factor-kB,they also decrease antigen presentation, expression of proin-flammatory cytokines and cell adhesion molecules, and chemo-taxis. In a concentration-dependent manner they inhibit mastcell activation and histamine release; although the mechanismsinvolved have not yet been delineated fully, downregulation ofintracellular calcium ion accumulation seems to play a role(Fig 3).1,8,16,18,27-30

H1-antihistamines are functionally classified into 2 groups.First-generation medications readily cross the blood-brain barrier(BBB) and occupy H1-receptors located on postsynaptic mem-branes of histaminergic neurons throughout the CNS. Second-generation H1-antihistamines do not cross the BBB readily. Useof positron emission tomography (PET) to document H1-antihis-tamine penetration into the human brain constitutes a newstandard by which CNS H1-receptor occupancy can be directlyrelated to effects on CNS function (Fig 3 and Table II).1,18,31-33

CLINICAL PHARMACOLOGYOFH1-ANTIHISTAMINESPharmacokinetic studies provide clinically relevant informa-

tion about the rate and extent of H1-antihistamine absorption, me-tabolism, elimination, and drug interactions. Pharmacodynamicstudies provide clinically relevant information about the onset,extent, and duration of H1-antihistamine action.1,18,34-41

First (old)–generation H1-antihistaminesMost first-generation H1-antihistamines were introduced

before regulatory agencies existed and before clinical pharmacol-ogy studies of new medications were required. Information aboutpharmacokinetics and pharmacodynamics in healthy adults,elderly people, children, infants, and other vulnerable patientsis therefore not available for most of them, and few drug interac-tion studies have been performed with them (see Table E1 in thisarticle’s Online Repository at www.jacionline.org).1,18

Second (new)–generation H1-antihistaminesFormost second-generationH1-antihistamines, pharmacokinet-

ics have been extensively investigated in healthy adults, patientswith impaired hepatic or renal function, and elderly people, chil-dren, and infants. Their drug-drug, drug-food, and drug–herbalproduct interactions, if any, are well characterized and seldomclinically relevant (Table III and see Table E1).1,18,34-37

The pharmacodynamics of most orally administered second-generation H1-antihistamines have been assessed by measuringsuppressionof the histamine-inducedwheals andflares (erythema),which correlates better with H1-receptor occupancy by free un-bound drug than with H1-antihistamine concentrations in plasmaor even in tissue. Duration of action is at least 24 hours, facilitatingonce-daily dosing. Tolerance does not occur during regular use.After discontinuation of regular daily dosing, residual effects,

such as suppression of allergy skin test responses, last from 1 to 5days (Table III and see Table E1).1,34,37-41

FIG 2. Molecular basis of action of histamine and antihistamines. A, The in-

active state of the histamine H1-receptor is in equilibrium with the active

state. B, The agonist, histamine, has preferential affinity for the active state,

stabilizes the receptor in this conformation, and shifts the equilibrium

toward the active state. C, An H1-antihistamine (inverse agonist) has

preferential affinity for the inactive state, stabilizes the receptor in this

conformation, and shifts the equilibrium toward the inactive state.15,18

GDP, Guanosine diphosphate; GTP, guanosine triphosphate.

J ALLERGY CLIN IMMUNOL

DECEMBER 2011

1142 SIMONS AND SIMONS

In patients with allergic rhinitis and allergic conjunctivitis,suppression of the response to nasal or conjunctival allergenchallenge tests by H1-antihistamines regardless of route of adminis-tration provides clinically relevant information about their onset, ex-tent, and duration of action. Although some systemic absorption ofnasal and ophthalmic formulations occurs, no dose adjustments arerequired in the elderly or other vulnerable populations, and no clin-ically relevant drug-drug, drug-food, or drug–herbal product interac-tions have been described. Despite different elimination half-lifevalues (see Table E1), most of these H1-antihistamine formulationsare administered at 8- to 12-hour intervals because of washout bysecretions on the nasal mucosa and conjunctivae.1,18,26-28

EFFICACY OF H1-ANTIHISTAMINESH1-antihistamines are widely used in the treatment of allergic

and nonallergic disorders (Fig 4).1,18,33,42-91

Allergic diseases in which H1-antihistamines are

medications of choiceFew clinical trials of first-generation H1-antihistamines in pa-

tients with allergic diseases meet current standards. In contrast,use of second-generation H1-antihistamines in patients withallergic rhinitis, allergic conjunctivitis, and chronic urticaria issupported by hundreds of well-designed, randomized, placebo-controlled trials lasting for weeks or months.1,18,37,42-72 Dosage

recommendations for oral, nasal, and ophthalmic H1-antihista-mine formulations in adults, children, and infantswith allergic rhi-nitis, allergic conjunctivitis, and urticaria are provided in Table E2in this article’s Online Repository at www.jacionline.org.42

Allergic rhinitis. The morbidity and economic impact ofallergic rhinitis are widely underestimated. In patients with thisdisease, oral second-generation H1-antihistamines prevent and re-lieve the sneezing, itching, and rhinorrhea that characterize theearly response to allergen, with a small beneficial effect on the na-sal congestion that characterizes the late allergic response (Fig 4).Efficacy is documented primarily by standardized symptomscores and quality-of-life assessments.1,18,37,42-46,50-56 Someoral H1-antihistamines are marketed in fixed-dose combinationwith the decongestant pseudoephedrine (see Table E2).42,53

Oral H1-antihistamines are more efficacious than chromonesand montelukast; however, all these classes of medications areless efficacious than nasal glucocorticoids. H1-antihistaminesare generally ineffective in patients with nonallergic rhinitis.56,57

NasalH1-antihistamine formulations have amore rapid onset ofaction than oral H1-antihistamine formulations (eg, 15minutes fornasal azelastine vs 150minutes for oral desloratadine). In patientswith seasonal allergic rhinitis, nasal H1-antihistamines are re-ported to be as efficacious ormore efficacious than oralH1-antihis-tamines, particularly for relief of nasal congestion. They improvesymptoms in patients who are unresponsive to oral H1-antihista-mines and those with vasomotor rhinitis. Patient preferenceshould be considered when recommending a nasal versus anoral H1-antihistamine (see Table E2). Nasal azelastine combinedwith nasal fluticasone in a single nasal spray delivery device is re-ported to provide significantly greater improvement of symptoms,including congestion, than either medication alone.26,42,56,58-60

Allergic conjunctivitis. In patients with allergic conjuncti-vitis, H1-antihistamines administered orally or directly to the con-junctivae relieve the itching, erythema, tearing, and edema thatcharacterize the early response to allergen (Fig 4).27,28,42,47,61-63

Ophthalmic formulations have a rapid onset of action (3-15 min-utes), and some of them are reported to benefit nasal symptoms inaddition to conjunctival symptoms. In patients with allergic con-junctivitis, H1-antihistamines have a more favorable benefit/riskratio than all other classes of medications, including ophthalmicnonsteroidal anti-inflammatory drugs, ophthalmic decongestants,and ophthalmic glucocorticoids (see Table E2).27,28,42,47,61-63

Urticaria. In patients with acute urticaria lasting less than 6weeks or chronic urticaria lasting 6 weeks or more, H1-antihista-mines decrease itching and reduce the number, size, and durationof wheals and flares (erythema, Fig 4). In patients with acuteurticaria, H1-antihistamines have not been optimally studied;however, in randomized double-blind placebo-controlled trialslasting 18 months, cetirizine and levocetirizine are reported toreduce acute urticaria in young atopic children.1,18,48,49,64

In patients with chronic urticaria, first-generation H1-antihista-mines are used despite the absence of satisfactory randomized,placebo-controlled trials to support their efficacy and safety. In con-trast, high-quality trials of second-generation H1-antihistamines,such as cetirizine, desloratadine, fexofenadine, levocetirizine,loratadine, bilastine, and rupatadine confirm that they decreasesymptoms and improve quality of life (see Table E2).42,48,65-69

Althoughmany patients respond to standard doses of these medica-tions, more respond to increasing the daily dose up to 4-fold; for ex-ample, in one double-blind randomized controlled trial, 13 of 40patients became symptom free on 5 mg of levocetirizine and 28

FIG 3. Benefits and risks of H1-antihistamines.A,Beneficial effects: H1-antihistamines act directly to interfere

with histamine action at H1-receptors on sensory neurons and small blood vessels, mainly post-capillary

venules. They also downregulate allergic inflammation indirectly through nuclear factor-kB (NF-kB) andthrough calcium ion channels. B, Potential adverse effects: First (old)–generation H1-antihistamines cross

the BBB and occupy CNS H1-receptors, as documented by means of PET. High H1-receptor occupancy cor-

relates directly with impairment of CNS function, with or without accompanying sedation. These medica-

tions also potentially cause adverse effects through other mechanisms, such as their antimuscarinic and

antiserotonin effects.1,7,18,31-33 DAG, 1,2-diacylglycerol; ER, endoplasma reticulum;GDP, guanosine diphos-

phate; GTP, guanosine triphosphate; IKr, rapid component of the delayed outward rectifying potassium

channel; INa, rapid component of the inward rectifying sodium channel; IP3, inositol 1,4,5-triphosphate;PIP2, phosphatidylinositol 4,5-bisphosphate; PKCb, protein kinase C b; PLCb, phospholipase C b.

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SIMONS AND SIMONS 1143

of the 40 patients became symptom free on 10 or 20 mg of levoce-tirizinewithout experiencing adverseeffects at the higher doses.Ad-ditionally, in objective tests, such as in patients with acquired coldurticaria, high-dose desloratadine (20mg) or rupatadine (20mg) de-crease wheal volume and improve cold provocation thresholds sig-nificantly compared with standard doses.70,71 Treatment guidelinesfor chronicurticarianowrecommendsecond-generationH1-antihis-tamines as the medications of choice, starting with standard dosesand increasing the doses up to 4-fold as needed toprovide relief.48,72

This approach has not yet been validated in children.49

For patients with severe chronic urticaria refractory to non-sedating H1-antihistamines, it can be helpful to add an H2-antihis-tamine, montelukast, omalizumab, cyclosporine, or dapsone andtreat exacerbations with a glucocorticoid for 3 to 7 days.48,72

Other. Small randomized controlled trials support the use ofH1-antihistamines to prevent and relieve itching and flushing inpatients with mastocytosis, prevent and relieve itchy large local

allergic reactions to mosquito bites, and reduce adverse reactionsandmodulate allergen-specific immune responses during stinginginsect venom immunotherapy.73-75

Diseases in which H1-antihistamines are not

medications of first choiceLargely on the basis of tradition, H1-antihistamines remain

widely used in many diseases in which the evidence base for theirefficacy and safety is weak and generally not supported by ran-domized controlled trials that meet current standards (Fig 4).76-91

Atopic dermatitis. Histamine acts as a pruritogen throughH4-receptors in patients with atopic dermatitis, and other media-tors, including IL-31 and other cytokines, play an important role.No high-quality randomized controlled trials of H1-antihistaminesconfirm their efficacy in patients with atopic dermatitis. Despitethe absence of such trials, first-generation H1-antihistamines are

TABLE II. H1-antihistamines: chemical and functional classification1,18

Chemical class

Functional class

First (old) generation Second (new) generation

Alkylamines Brompheniramine, chlorpheniramine, dexchlorpheniramine,

dimethindene�, pheniramine, triprolidine*

Acrivastine*

Piperazines Buclizine, cyclizine, hydroxyzine*, meclizine, oxatomide� Cetirizine*, levocetirizine*

Piperidines Azatadine, cyproheptadine, diphenylpyraline, ketotifen Astemizole�, bepotastine, bilastine�, desloratadine*,ebastine�, fexofenadine*, levocabastine�, loratadine*,mizolastine�, rupatadine*�, terfenadine*�, alcaftadine

Ethanolamines Carbinoxamine, clemastine, dimenhydrinate, diphenhydramine,

doxylamine, phenyltoloxamine�-

Ethylenediamines Antazoline, pyrilamine, tripelennamine -

Phenothiazines Methdilazine, promethazine -

Other Doxepin� Azelastine, emedastine, epinastine, olopatadine

*Some of the H1-antihistamines listed above are related to each other; for example, acrivastine is a derivative of triprolidine, cetirizine is a metabolite of hydroxyzine, levocetirizine

is an enantiomer of cetirizine, and desloratadine is a metabolite both of loratadine and rupatadine. Of the H1-antihistamines currently approved for use in the United States,

cetirizine, levocetirizine, desloratadine, fexofenadine, and loratadine (listed in boldface) are the most thoroughly investigated in randomized controlled trials and other prospective

studies.

�In the United States these H1-antihistamines are either not yet approved or have never been approved. Regulatory approval was withdrawn for astemizole and terfenadine in the 1990s.

�Doxepin has dual H1- and H2-antihistamine activities and is classified as a tricyclic antidepressant. The standard dose for urticaria is 25 to 50 mg 3 times daily; yet a considerably

lower dose, 1 to 3 mg of doxepin once daily, is effective for insomnia in the elderly.

TABLE III. Orally administered second (new)–generation

H1-antihistamines: clinical pharmacology1,18

Pharmacokinetics*

Absorption: Maximum serum concentrations are reached at 0.8 to 3 hours.

Metabolism: Ranges from minimal (fexofenadine) to extensive

(desloratadine and rupatadine).

Elimination: Terminal elimination half-life values range from 6 to 27 hours.

Pharmacokinetics are minimally influenced by age, hepatic dysfunction,

and renal dysfunction.

Clinically relevant interactions seldom occur with other drugs, foods, or

herbal products.

Pharmacodynamics*��§Studied with suppression of histamine-induced wheals and flares.�Studied with suppression of symptoms after allergen challenge in allergic

rhinitis and allergic conjunctivitis.�Onset of action ranges from 0.7 to 2.6 hours.

Extent of action (potency) ranges from 75% to 100%.

Duration of action is typically >_24 hours.�Receptor affinity: Studied for some, but not all, second-generation

H1-antihistamines.§

Receptor occupancy by free (unbound) drug: Determined for some, but

not all, second-generation H1-antihistamines.§

*Please see Table E1 for additional information. Despite differences in

pharmacokinetics and pharmacodynamics, the doses of many orally administered

second-generation H1-antihistamines are similar or even identical, which is

attributable in part to the wide margin of safety of these medications.

�Suppression of wheals and flares and symptoms lasts for hours after serum or plasma

H1-antihistamine concentrations are undetectable. Wheal and flare suppression studies

correlate well with the efficacy of orally administered H1-antihistamines in patients

with urticaria but less well in patients with allergic rhinitis or allergic conjunctivitis.

�Allergen challenge studies are typically conducted in patients with a predetermined

symptom score after allergen priming and involve a short duration of exposure and

follow-up.

§Those studied include desloratadine, fexofenadine, and levocetirizine.

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1144 SIMONS AND SIMONS

still sometimes used for their sedative effects.Optimalmedicationsfor atopic dermatitis include topical glucocorticoids, topical calci-neurin inhibitors, agents to restore the skin barrier, and, whenneeded, antimicrobial agents.1,18,76

Asthma. H1-antihistamines might provide indirect benefit inpatients with concomitant seasonal asthma and allergic rhinitis;

however, they are not medications of choice in asthmatic patients.Moderate-to-severe persistent asthma is optimally controlledwithan inhaled glucocorticoidwith orwithout a long-actingb-adrener-gic agonist (in the same inhalation device) or montelukast, and ashort-acting b-agonist to relieve breakthrough symptoms.1,18,77

Anaphylaxis. A Cochrane systematic review of 2070 pub-lications on H1-antihistamines in the treatment of anaphylaxisdid not identify any randomized controlled trials that providedsatisfactory evidence for their use in this disease. The onset ofaction of orally administered H1-antihistamines is slow (0.7-2.6hours). Although they decrease itch and hives, they do not pre-vent or relieve laryngeal edema, lower respiratory tract obstruc-tion, or shock and are not life-saving. Epinephrine (adrenaline)is the initial medication of choice.78

Nonallergic angioedema. In the absence of itching orurticaria, angioedema is typically nonallergic, not mediated byhistamine, and not prevented or relieved by H1-antihistamines.Treatment of hereditary angioedema types I, II, and III involvesC1-esterase inhibitor concentrates, ecallantide, or icatibant. Treat-ment of angiotensin-converting enzyme inhibitor–associated non-allergic angioedema involves medication substitution, whenpossible. Treatment of malignancy-associated nonallergic angioe-dema focuses on definitive treatment of the malignancy.79

Other disorders. H1-antihistamines are used to treat symp-toms of upper respiratory tract infections, acute otitis media, otitismedia with effusion, sinusitis, nasal polyps, nonspecific cough,and nonallergic, nonspecific itching; however, their efficacy andsafety have not been confirmed in high-quality randomized con-trolled trials in patients with any of these disorders.1,18,57,80-85

Central nervous system and vestibular disordersThe first-generation H1-antihistamines diphenhydramine, dox-

epin, doxylamine, and pyrilamine are the most widely used med-ications in the world for preventing and relieving insomnia, evenwhen given in low doses, such as 25 mg of diphenhydramine or1 to 3 mg of doxepin once daily at bedtime. In medical settings,diphenhydramine, hydroxyzine, and promethazine are given

FIG 4. Science versus reality: evidence-based use of H1-antihistamines in allergic diseases and other disor-

ders. On the basis of well-designed randomized controlled trials and meta-analyses of such trials, the evi-

dence base for the efficacy and safety of second (new)–generation H1-antihistamines is strong in patients

with allergic rhinitis, allergic conjunctivitis, and urticaria (category of evidence I, strength of recommenda-

tion A) but not in those with atopic dermatitis and other diseases (category of evidence II-IV, strength of

recommendation B, C, or D, depending on the disease). The evidence base for the efficacy and safety of first

(old)–generation H1-antihistamines remains weak in patients with allergic rhinitis, allergic conjunctivitis, ur-

ticaria, atopic dermatitis, and other diseases, including CNS and vestibular disorders (category of evidence

II-IV, strength of recommendation B, C, or D, depending on the disease). Their potential adverse effects

remain a concern.1,18,33,42-91

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(often in combination with other medications) for conscious seda-tion, perioperative sedation, and analgesia. They are also used fortreatment of serotonin syndrome, anxiety, acute agitation,akathisia, and migraine headaches.1,18,86-88

Dimenhydrinate, diphenhydramine, meclizine, and prometha-zine block the histaminergic signal from the vestibular nucleus tothe vomiting center in the medulla. They are used for preventionand treatment of nausea and vomiting during pregnancy, chemo-therapy, and the postoperative period and for prevention andtreatment of motion sickness, vertigo, and related disorders.Commercial airline pilots and military pilots are prohibited fromusing them before or during flights because of their potentialCNS-related adverse effects.1,18,89-91

ADVERSE EFFECTS OF H1-ANTIHISTAMINES

First (old)–generation H1-antihistaminesFirst-generation H1-antihistamines potentially cause adverse

effects in multiple body systems (Fig 3). They have poor selectiv-ity for the H1-receptor. Their antimuscarinic effects include my-driasis, dry eyes, dry mouth, constipation, and urinary hesitancyand retention. Their antiserotonin effects include increased appe-tite and weight gain. Their anti–a-adrenergic effects include diz-ziness and orthostatic hypotension.1,18,92,93 They have also beenimplicated in impairing the innate immune response to bacterialinfection94; however, this is more likely attributable to coadminis-tered H2-antihistamines.95

For 70 years, H1-antihistamines have been marketed to themedical profession and the general public as safe medications, de-spite the voluminous medical literature documenting their CNS

adverse effects and toxicity (Table IV).1,7,18,31-33,96-105 As previ-ously noted, their CNS adverse effects are due to inverse agonismat CNSH1-receptors, inhibition of neurotransmission in histamin-ergic neurons, and impairment of alertness, cognition, learning,and memory that is not necessarily associated with sedation,drowsiness, fatigue, or somnolence.Standard doses. PET studies with 11C-doxepin as the

positron-emitting ligand (positive control) confirm that in stan-dard or even low doses, first-generation H1-antihistamines crossthe BBB. In standard doses, they typically occupy more than70% of CNS H1-receptors. High H1-receptor occupancy is asso-ciated with decreased histaminergic neurotransmission and im-paired CNS function on objective tests.31-33,96-98 Penetration ofthe BBB is related to lipophilicity, relatively low molecularweight, and lack of substrate recognition by the P-glycoproteinefflux pump expressed on the luminal surfaces of nonfenestratedendothelial cells in the CNS vasculature.Even in low doses, eg, 2 mg of chlorpheniramine or 25 mg of

diphenhydramine, first-generation H1-antihistamines potentiallyimpair alertness, cognition, learning, and rapid response/wakingmemory, especially during complex sensorimotor tasks, includingdivided attention, critical tracking, and attention-switch tasks,and objectively monitored car driving.99-101 Impairment of CNSfunction can occur in asymptomatic persons.1,18,33,96-98 Whentaken at bedtime, first-generation H1-antihistamines increase thelatency to onset of restful rapid eye movement sleep and reducethe duration of rapid eye movement sleep (Table IV).33,102 Inpatients who have CNS residual effects the next morning (anantihistamine ‘‘hangover’’), PET documents residual H1-receptoroccupancy.32 Tolerance to adverse CNS effects might or might

TABLE IV. H1-antihistamines: potential adverse effects1,7,18,33,106-126

First (old) generation*y Second (new) generationyzCNS

Mechanism: inhibition of the neurotransmitter

effect of histamine at CNS H1-receptors

After standard doses, there is potential

impairment of alertness, cognition, learning,

memory, and performance (especially of

complex sensorimotor tasks), with or without

drowsiness, somnolence, fatigue, or sedation.

Other potential CNS adverse effects include

headache, dizziness, confusion, agitation,

behavioral changes (children), and, less

commonly, dystonia, dyskinesia, and

hallucinations.

Minimal or no adverse effects are reported with

5 mg of cetirizine, 5 mg of desloratadine,

360 mg of fexofenadine (off-label), 5 mg of

levocetirizine, 10 mg of loratadine, or 10 mg

of rupatadine. At higher doses, with the

exception of fexofenadine, these H1-

antihistamines might cause dose-related CNS

effects in some adults with some allergic

diseases.

Cardiac

Mechanisms: antimuscarinic effects, anti–a-

adrenergic effects, and blockade of cardiac

ion currents (IKr, INa, Ito, IK1 and IKs)

Dose-related sinus tachycardia; reflex

tachycardia, prolonged atrial refractive

period, and supraventricular arrhythmias

potentially occur. Prolongation of the QTc

interval and ventricular arrhythmias have

been reported after standard doses but are

more likely to occur after overdose (see the

‘‘Toxicity after overdose’’ section).

Concerns are minimal in countries in which

regulatory agencies scrutinize second-

generation H1-antihistamines for potential

cardiac toxicity and do not approve them for

use if this is identified.

Other

Mechanisms: blockade of muscarinic, serotonin,

and a-adrenergic receptors; unknown§

After standard doses, potential antimuscarinic

effects include mydriasis (dilation of pupils),

blurred vision, dry eyes, dry mouth, urinary

retention and hesitancy, constipation, erectile

dysfunction, and memory deficits; these

H1-antihistamines are contraindicated in

persons with glaucoma or prostatic

hypertrophy. Antiserotonin effects include

appetite stimulation and weight gain

(especially with cyproheptadine and

ketotifen). Anti–a-adrenergic effects include

peripheral vasodilation, orthostatic

hypotension, and dizziness.

None

Toxicity after overdose

Mechanisms: multiple

In adults potential CNS effects include extreme

drowsiness, confusion, delirium, coma, and

respiratory depression. In infants and young

children paradoxical excitation, irritability,

hyperactivity, insomnia, hallucinations, and

seizures can precede coma and respiratory

depression. Prolongation of the QTc interval

and ventricular arrhythmias have been

reported after overdose of cyproheptadine,

diphenhydramine, doxepin, hydroxyzine,

promethazine, and others. Adverse CNS

effects typically predominate over adverse

cardiac effects. In untreated patients, death

can occur within hours.

Up to 30-fold overdoses of cetirizine,

fexofenadine, and loratadine have not been

causally associated with serious adverse

events or fatality.

Drug abuse

Mechanisms: through H1-receptors and other

receptors in the CNS

Euphoria, hallucinations, and ‘‘getting high’’ are

reported for cyclizine, diphenhydramine,

dimenhydrinate, and others.

None reported

IK1, Inward rectifying current; IKr, rapid component of the delayed outward rectifying potassium current; IKs, slow component of the delayed outward rectifying potassium current;

INa, rapid component of the inward rectifying sodium current; Ito, transient outward potassium current.

*Information about adverse effects and toxicity of first-generation H1-antihistamines is based largely on descriptions in case reports and case series published since the 1940s.

Promethazine is no longer recommended because it potentially causes sedation and respiratory depression/arrest. Additionally, through the intravenous route, it can cause vascular

irritation, local necrosis, and gangrene. Diphenhydramine or doxepin, applied topically to the skin, potentially cause contact dermatitis; when applied to abraded or thin skin, they

can also cause systemic adverse effects and, rarely, fatality.

�Nasal and ophthalmic formulations of H1-antihistamines are minimally absorbed and seldom cause systemic adverse effects; however, some patients report a transient bitter or

unpleasant taste sensation. Ophthalmic H1-antihistamines can cause stinging or burning on application. These H1-antihistamines should be applied at least 10 minutes before

contact lens insertion because the preservative benzalkonium chloride 0.01% in the formulations can cloud the lenses.

�Information about relative lack of adverse effects from second-generation H1-antihistamines is based on information obtained in prospective, randomized, placebo-controlled

trials in patients with allergic rhinitis and chronic urticaria and on occasional case reports of overdose with remarkable absence of toxicity.

§Both first- and second-generation H1-antihistamines are reported to cause rare adverse effects for which the mechanisms are incompletely understood. These include

agranulocytosis, anaphylaxis, fever, fixed-drug eruption, liver enzyme elevation/hepatitis, photosensitivity, and urticaria. Rhabdomyolysis has been reported after overdose.

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not occur with regular daily use.33 The adverse CNS effects ofconcurrently ingested ethanol, benzodiazepines, and otherCNS-active chemicals are potentially exacerbated.1,18,33 Addi-tionally, diphenhydramine and others are documented drugs ofabuse.105

The unfavorable therapeutic index of systemically administeredfirst-generation H1-antihistamines has been well documented invulnerable patients, such as those with impaired hepatic or renalfunction (including patients receiving hemodialysis), elderly peo-ple, youngchildren, and infants (seeTableE3 in this article’sOnlineRepository at www.jacionline.org).1,7,18,33,106-117

Toxicity after overdose. Accidental or intentional first-generation H1-antihistamine overdose potentially leads toextreme drowsiness, confusion, delirium, coma, respiratory de-pression, and, in the absence of supportive treatment, fatality.In infants and young children, paradoxical CNS excitationwith irritability, hyperalertness, insomnia, hallucinations, andseizures might precede drowsiness and other CNS symptoms(Table IV).1,7,18,33

Cardiac toxicity of H1-antihistamines does not occur through theH1-receptor and is not a class effect. Rather, it is due to blockade ofcardiac ion currents, such as the rapid component of the delayedoutward rectifying potassiumchannel (IKr) and the outward rectify-ing current or the rapid component of the inward rectifying sodiumchannel (INa). After an overdose, some first-generation H1-antihis-tamines (eg, 0.5-1 g of diphenhydramine taken by an adult attempt-ing suicide) potentially lead to sinus tachycardia, prolongationof the QT interval, ventricular arrhythmias, and torsade depointes.1,18,33,118-120 Diphenhydramine overdoses are so frequentlyreported to poison control centers in theUnited States that validatedevidence-based guidelines have been developed for their triage andmanagement.121,122 In infants and young children first-generationH1-antihistamines are causally linked with deaths from accidentaloverdose and with homicide (Table IV).1,7,18,33,115-117,121,122

Second (new)-generation H1-antihistaminesIn contrast to first-generation H1-antihistamines, second-

generation H1-antihistamines are relatively free from antihista-minic adverse CNS effects and from antimuscarinic, antiserotonin,and anti–a-adrenergic effects (Table IVand see Table E3).1,18,33

Standard doses. Second-generationH1-antihistamines crossthe BBB to a minimal degree, penetrate poorly into the CNS, andtypically occupy fewer than 20% of CNS H1-receptors, as docu-mented by PET. Fexofenadine is least likely to cross the BBB oroccupy CNS H1-receptors and is consistently nonimpairing andnonsedating, even in a high off-label dose of 360mg. It is thereforethe H1-antihistamine of choice for airline pilots and others insafety-critical occupations and/or performing activities requiringoptimal alertness, cognition, memory, and multi-tasking. Dose-dependent CNS H1-receptor occupancy has been documented forcetirizine and others. Second-generation H1-antihistamines donot exacerbate the CNS effects of concurrently used ethanol, ben-zodiazepines, and other CNS-active substances.1,18,31,33,96-98,123

About 15 years ago, regulatory agencies rescinded theirapproval for astemizole and terfenadine, the second-generationH1-antihistamines initially introduced, because they potentiallycause QT interval prolongation and torsade de pointes. Subse-quently, regulatory agencies have scrutinized all second-generation H1-antihistamines for their proarrhythmic potentialand required studies of their cardiac safety at standard doses and

high off-label doses, as well as drug interaction studies and studiesin the elderly and other vulnerable patients. H1-antihistamines thatfail this scrutiny are not approved for use (Table IV).1,18,124,125

Long-term safety of the second-generation H1-antihistaminescetirizine, desloratadine, fexofenadine, levocetirizine, and lorata-dine has been documented in randomized controlled trials lasting6 to 18 months in adults and in children as young as 1 to 2 yearsold.1,18,126

Lack of toxicity after overdose. Massive overdosesof second-generation H1-antihistamines, such as cetirizine, fexo-fenadine, and loratadine, have not been causally linked with sei-zures, coma, respiratory depression, or fatality (Table IV).1,18,33

FUTURE DIRECTIONSIn the future, H1-antihistamines will continue to be a cor-

nerstone of pharmacologic treatment in patients with allergicrhinitis, allergic conjunctivitis, and urticaria. Novel agents,such as rupatadine, an H1-antihistamine/anti–platelet-activat-ing factor agent,23,24,66,71,123,125 might play a unique role.H3-antihistamines lead to an increase in norepinephrine andmight have an advantageous decongestant effect in patientswith allergic rhinitis administered with or without H1-antihis-tamines.17,127-131 H4-antihistamines might play an importantrole in the downregulation of inflammation in patients withallergic rhinitis, administered with or without H1-antihista-mines, and in patients with atopic dermatitis, asthma, andother chronic inflammatory diseases.17,127,128,131-134

We thank Jacqueline Schaffer, MAMS, for illustrating key concepts in the

text. We also acknowledge the assistance of Lori McNiven.

What do we know?d At H1-receptors, the molecular mechanisms of action of

histamine and H1-antihistamines involve inverse agonism.

d H1-antihistamines are functionally classified into first(old)–generation, potentially impairing, sedating medica-tions and second (new)–generation, relatively nonimpair-ing, nonsedating medications.

d Use of PET to study H1-antihistamine penetration in thehuman brain is a major breakthrough; now CNS H1-re-ceptor occupancy can be directly related to CNS func-tional effects.

d Orally administered first (old)–generation H1-antihista-mines are no longer medications of choice in patientswith allergic rhinitis, allergic conjunctivitis, and chronicurticaria.

d In patients with allergic rhinitis, orally administered sec-ond (new)–generation H1-antihistamines are among themedications of choice, as are nasal H1-antihistamines thatprovide rapid relief of symptoms, including congestion.

d In patients with allergic conjunctivitis, H1-antihistaminesare the medications of choice, either administered orally,or by means of ophthalmic application which relievessymptoms within minutes through antihistaminic and an-tiallergic (mast cell stabilization) effects.

d In patients with chronic urticaria, second-generation H1-antihistamines are the medications of choice. With someof these medications, such as levocetirizine, increasing

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1148 SIMONS AND SIMONS

the dose up to 4-fold significantly improves efficacy with-out compromising safety.

d H1-antihistamines are not medications of choice for atopicdermatitis, asthma, anaphylaxis, nonallergic angioedema,colds, otitis media, sinusitis, nasal polyps, nonspecificcough, or nonallergic, nonspecific itch, in which their effi-cacy and safety have not been documented in high-qualityrandomized controlled trials.

d For insomnia and other CNS disorders and for motionsickness and other vestibular disorders, first-generationimpairing, sedating H1-antihistamines remain in wide-spread use, despite safety concerns.

d Orally administered first-generation H1-antihistaminesare contraindicated in anyone who requires alertness, in-tellectual prowess, and ability to perform complex senso-rimotor tasks.

What is still needed?d Additional studies of the molecular mechanisms of action

of H1-antihistamines as inverse agonists (not as antago-nists or blockers) at the H1-receptor, including studiesof the molecular basis of their specificity for this receptor

d Additional clinical pharmacology studies and randomizedcontrolled trials of second (new)–generationH1-antihistamineefficacy and safety in the elderly and in infants and children

d Additional randomized controlled trials in which second(new)–generation H1-antihistamines are compared witheach other in patients with allergic rhinitis, allergic con-junctivitis, and chronic urticaria

d Additional high-quality randomized controlled trials ofsecond-generation H1-antihistamines for the preventionand relief of mastocytosis-associated itching and flushingand the prevention of allergic reactions

d Additional comparative PET studies of first- and second-generation H1-antihistamines in order to correlate BBBpenetration and CNS H1-receptor occupancy with CNSfunctional effects

d Ongoing documentation of the safety of second-generation H1-antihistamines in pregnancy

d Accelerated investigation of H3-antihistamines and H4-antihistamines in allergic diseases, given either alone orwith H1-antihistamines

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TABLE E1. H1-antihistamines: pharmacokinetics and pharmacodynamics in healthy adults18

A. Orally administered

H1-antihistamines

Time to maximum

plasma concentration (h)

after a single dose

Terminal elimination

half-life (h)

Clinically relevant

drug-drug interactions*

Onset of

action (h)yDuration of

action (h)yFirst (old) generation

Chlorpheniramine� 2.8 6 0.8 27.9 6 8.7 Possible 3 24

Diphenhydramine� 1.7 6 1.0 9.2 6 2.5 Possible 2 12

Doxepin� 2 13 Possible NA NA

Hydroxyzine� 2.1 6 0.4 20.0 6 4.1 Possible 2 24

Second (new) generation

Bilastine 1.2 14.5 Unlikely 2 24

Cetirizine 1.0 6 0.5 6.5-10 Unlikely 0.7 >_24

Desloratadine 1-3 27 Unlikely 2-2.6 >_24

Fexofenadine* 1-3 11-15 Unlikely 1-3 24

Levocetirizine 0.8 6 0.5 7 6 1.5 Unlikely 0.7 >24

Loratadine (metabolite:

descarboethoxyloratadine)

1.2 6 0.3 (1.5 6 0.7) 7.8 6 4.2 (24 6 9.8) Unlikely 2 24

Rupatadine 0.75-1.0 6 (4.3-14.3) Unlikely 2 24

B. Nasal/ophthalmic

H1-antihistamines

Time to maximum

plasma concentration (h)

after a single dose§

Terminal elimination

half-life (h)§

Clinically relevant

drug-drug interactions§

Onset of

action (h){Duration of

action (h){

Alcaftadine (ophthalmic) 0.25 8-12 No 0.05 24

Azelastine (metabolite:

des-methylazelastine, nasal

and ophthalmic)

5.3 6 1.6 (20.5) 22-27.6 (54 6 15) No 0.5 12

Bepotastine (ophthalmic) 1.2 2.5 No 0.25 12-24

Emedastine (ophthalmic) 1.4 6 0.5 7 No 0.25 12

Epinastine (ophthalmic) 2 6.5 No 0.1 12

Ketotifen (ophthalmic) 2-4 20-22 No 0.25 12

Levocabastine (ophthalmic) 1-2 35-40 No 0.25 12

Olopatadine (nasal and ophthalmic) 0.5-2 8-12 No 0.25 12-24

Results are expressed as means 6 SDs, unless otherwise indicated.

NA, Information not available or incomplete.

*Clinically relevant drug-drug interactions are unlikely with most of the second-generation H1-antihistamines. Clinically relevant drug-food interactions have been well studied for

fexofenadine. Naringin, a flavonoid in grapefruit juice, and hesperidin, a flavonoid in orange juice, reduce the oral bioavailability of fexofenadine through inhibition of OATP 1A2.

This interaction can be avoided by waiting for 4 hours between juice consumption and fexofenadine dosing.

�Onset/duration of action is based on wheal and flare studies.

�Six or seven decades ago, when many of the first-generation H1-antihistamines were introduced, pharmacokinetic and pharmacodynamic studies were not required by regulatory

agencies. They have subsequently been performed for some of these drugs; however, empiric dosage regimens persist. For example, the manufacturers’ recommended

diphenhydramine dose for allergic rhinitis is 25 to 50 mg every 4 to 6 hours, and the diphenhydramine dose for insomnia is 25 to 50 mg at bedtime. Despite the long terminal

elimination half-life values identified for some of the medications (eg, >24 hours for chlorpheniramine), based on tradition, extended release formulations remain in use.

§Nasal and ophthalmic H1-antihistamines: time to maximum plasma concentration, terminal elimination half-life, and drug-drug interaction information are based on serum levels

obtained after oral administration because serum levels after topical application are too low to permit calculation of pharmacokinetic parameters; most of these medications cause

minimal or no skin test suppression.

{Nasal and ophthalmic H1-antihistamine formulations: onset and duration of action are based on standard adult doses (eg, 1-2 sprays in each nostril or 1 drop in each eye

determined in nasal and conjunctival challenge studies, respectively).

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TABLE E2. H1-antihistamines: recommended doses for oral, nasal, and ophthalmic use in adults, children, and infants42

A. Oral second (new)–generation H1-antihistamines* Formulations Usual daily adult dosage Usual daily pediatric dosage

Cetirizine�generic

Zyrtec

5- or 10-mg chew tabs; 10-mg tabs; 1 mg/1 mL syrup 5 or 10 mg 13/d 6-11 mo: 2.5 mg 13/d�12-23 mo: 2.5 mg 13/d-bid�2-5 y: 2.5 or 5 mg 13/d or 2.5 mg bid

6-11 y: 5-10 mg 13/d

Cetirizine/pseudoephedrine�Zyrtec-D 12 hour 5-mg/120-mg ER tabs 1 tab bid >_12 y: 1 tab bid

Desloratadine

Clarinex 5-mg tabs; 0.5 mg/mL syrup

2.5- or 5-mg disintegrating tabs

5 mg 13/d 6-23 mo: 1 mg 13/d§

2-5 y: 1.25 mg 13/d

6-11 y: 2.5 mg 13/d

Desloratadine/pseudoephedrine

Clarinex-D 12 hour, Clarinex-D 24 hour 2.5-mg/120-mg ER tabs

5-mg/240-mg ER tabs

1 tab bid

1 tab 13/d

>_12 y: 1 tab bid>_12 y: 1 tab 13/d

Fexofenadine�generic

Allegra

30-, 60-, or 180-mg tabs

60- or 180-mg tab; 30 mg/5 mL suspension; 30-mg disintegrating tab

60 mg bid or 180 mg 13/d 6-23 mo: 15 mg bid§

2-11 y: 30 mg bid

Fexofenadine/pseudoephedrine�Allegra-D 12 hour, Allegra-D 24 hour 60-mg/120-mg ER tabs

180-mg/240-mg ER tabs

1 tab bid

1 tab 13/d

>_12 y: 1 tab bid>_12 y: 1 tab 13/d

Levocetirizine

Xyzal 5-mg tabs; 0.5 mg/mL oral solution 5 mg 13/d 6 mo-5 y: 1.25 mg 13/dk6-11 y: 2.5 mg 13/d

Loratadine�generic

Claritin

Alavert

10-mg tabs; 10-mg disintegrating tabs; 1 mg/mL syrup and suspension

10-mg tabs; 1 mg/mL syrup;

5- or 10-mg disintegrating tabs; 10-mg caps

10-mg tabs; 10-mg disintegrating tabs

10 mg 13/d 2-5 y: 5 mg 13/dc

>_6 y: 10 mg 13/d

Loratadine/pseudoephedrine�Claritin-D 12 hour, Claritin-D 24 hour,

Alavert-D 12 hour

5-mg/120-mg ER tabs

10-mg/240-mg ER tabs

5-mg/120-mg ER tabs

1 tab bid

1 tab 13/d

1 tab bid

>_12 y: 1 tab bid>_12 y: 1 tab 13/d>_12 y: 1 tab bid

Adapted with special permission from Treatment Guidelines from the Medical Letter 2010;8:9-18; www.medicalletter.org.42

bid, Twice daily; ER, extended release; FDA, US Food and Drug Administration.

*Few medications from any class and no H1-antihistamines are designated FDA Pregnancy Category A. Cetirizine and loratadine are designated FDA Pregnancy Category B (to be used during pregnancy only

if the expected benefits to the mother exceed the unknown risk to the fetus). Fexofenadine, desloratadine, and levocetirizine are designated FDA Pregnancy Category C (animal studies negative, human data

not available, or animal studies positive, human data negative).

�Available without a prescription.

�Only approved for treatment of chronic idiopathic urticaria and perennial allergic rhinitis in this age group.

§Only approved for treatment of chronic idiopathic urticaria in this age group.

kNot approved for treatment of seasonal allergic rhinitis in children 2 years or younger.

(Continued)

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TABLE E2. (Continued)

B. H1-antihistamine

nasal sprays* Formulations Usual daily adult dosage Usual daily pediatric dosage

Azelastine

Astelin 0.1% Metered-dose pump spray (137 mg/spray) 1-2 sprays per nostril 23/d 5-11 y: 1 spray per nostril 23/d

Astepro 0.1%� Metered-dose pump spray (137 mg/spray) 1-2 sprays per nostril 23/d >_12 y: 1-2 sprays per nostril 23/d

Astepro 0.15% Metered-dose pump spray (205.5 mg/spray) 1-2 sprays per nostril 23/d� >_12 y: 1-2 sprays per nostril 23/d

Olopatadine

Patanase Metered-dose pump spray (665 mg/spray) 2 sprays per nostril 23/d >_12 y: 2 sprays per nostril 23/d

Adapted with special permission from Treatment Guidelines from the Medical Letter 2010;8:9-18; www.medicalletter.org.42

FDA, US Food and Drug Administration.

*Azelastine and olopatadine are designated FDA Pregnancy Category C (animal studies negative, human data not available, or animal studies positive, human data negative).

�FDA approved for the treatment of seasonal allergic rhinitis.

�Dosage for seasonal allergic rhinitis is 1 to 2 sprays per nostril twice daily or 2 sprays per nostril once daily. Dosage for perennial allergic rhinitis is 2 sprays per nostril twice daily.

C. Ophthalmic H1-antihistamines*y Formulations Available sizes Usual daily dosage Pediatric use

Alcaftadine

Lastacaft 0.25% solution 3 mL 1 drop 13/d >2 y

Azelastine

Optivar 0.05% solution 6 mL 1 drop bid >3 y

Bepotastine

Bepreve 1.5% solution 10 mL 1 drop bid >_2 y

Emedastine difumarate

Emadine 0.05% solution 5 mL 1 drop qid >_3 y

Epinastine

Elestat 0.05% solution 5 mL 1 drop bid >_3 y

Ketotifen fumarate�generic 0.025% solution 5 mL 1 drop every 8-12 h >_3 y

Zaditor 0.025% solution 5 mL 1 drop every 8-12 h >_3 y

Claritin Eye 0.025% solution 5 mL 1 drop every 8-12 h >_3 y

Eye Itch Relief 0.025% solution 5 mL 1 drop every 8-12 h >_3 y

Olopatadine

Pataday 0.2% solution 2.5 mL 1 drop 13/d >_3 y

Patanol 0.1% solution 5 mL 1-2 drops bid >_3 y

Adapted with special permission from Treatment Guidelines from the Medical Letter 2010;8:9-18; www.medicalletter.org.42

bid, Twice daily; ER, extended release; FDA, US Food and Drug Administration; qid, 4 times daily.

*Except for emedastine, H1-antihistamine ophthalmic formulations are also designated as antiallergic drugs.

�Alcaftadine and emedastine are designated FDA Pregnancy Category B (to be used during pregnancy only if the expected benefits to the mother exceed the unknown risk to the fetus). Azelastine, bepotastine, epinastine, ketotifen, and

olopatadine are designated FDA Pregnancy Category C (animal studies negative, human data not available, or animal studies positive, human data negative).

�Available over the counter.

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TABLE E3. H1-antihistamines: potential adverse effects in vulnerable patients1,7,18,106-126

First (old) generation Second (new) generation

Patients with impaired

hepatic or renal function

There are few prospective studies. In patients with

impaired hepatic or renal function, including those

undergoing hemodialysis, use of first-generation

H1-antihistamines in standard doses is potentially

associated with adverse effects, including CNS

effects such as impaired cognitive function and

drowsiness.

The clinical pharmacology (absorption, distribution,

metabolism, and elimination) of most of these

medications has been studied prospectively in

patients with impaired hepatic or renal function. If

necessary, specific instructions for reduction in dose

or dose frequency are provided.

Elderly people There are few randomized controlled trials of first-

generation H1-antihistamines in the elderly. These

medications are commonly used in this population, in

which they potentially impair cognition and memory

and cause inattention, disorganized speech, falls,

incontinence, altered consciousness, and delirium.

The clinical pharmacology of most second-generation

H1-antihistamines has been studied prospectively in

the elderly. If necessary, specific instructions for

reduction in dose or dose frequency are provided.

Pregnant and lactating women With regard to teratogenicity, first-generation

H1-antihistamines are classified as FDA Pregnancy

Category B (chlorpheniramine and diphenhydramine)

or C (hydroxyzine and ketotifen). In nursing infants

they potentially cause irritability or drowsiness.

With regard to teratogenicity, second-generation

H1-antihistamines are classified as FDA Pregnancy

Category B (alcaftadine, cetirizine, emedastine, and

loratadine) or C (azelastine, bepotastine,

desloratadine, epinastine, fexofenadine,

levocetirizine, and olopatadine). No CNS adverse

effects have been reported in nursing infants.

Neonates When given to the mother immediately before

parturition, these medications potentially cause

irritability, drowsiness, and respiratory depression in

the neonate.

No CNS adverse effects have been reported in neonates.

Infants and young children For decades, first-generation H1-antihistamines have

been assumed to be effective and safe in infants and

children with allergies, coughs, and colds, either

when given alone or in a mixture containing other

drugs; however, they are often associated with

adverse effects and occasionally with fatalities.*

Regulatory agencies in the United States and other

countries have mandated that more than 500 pediatric

oral formulations containing first-generation

H1-antihistamines be withdrawn from the market.

The long-term safety of cetirizine, desloratadine,

fexofenadine, levocetirizine, and loratadine has been

confirmed in young children.

*First-generation H1-antihistamines, particularly in the phenothiazine class, have been associated with sudden infant death syndrome and apparent life-threatening events, although

causality has never been proved.

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Pharmacology & Therapeutics 178 (2017) 148–156

Contents lists available at ScienceDirect

Pharmacology & Therapeutics

j ourna l homepage: www.e lsev ie r .com/ locate /pharmthera

The clinical pharmacology of non-sedating antihistamines

Kazuhiko Yanai a,b, Takeo Yoshikawa a,⁎, Ai Yanai a, Tadaho Nakamura c, Tomomitsu Iida a,Rob Leurs d, Manabu Tashiro b

a Department of Pharmacology, Tohoku University School of Medicine, Sendai 980-8575, Japanb Cyclotron and Radioisotope Center, Tohoku University, Sendai 980-8578, Japanc Department of Pharmacology, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japand Amsterdam Institute of Molecules, Medicines and Systems, Department of Medicinal Chemistry, Vrije Universiteit Amsterdam, The Netherlands

⁎ Corresponding author at: Department of PharmacoloMedicine, 2-1 Seiryo-cho, Aoba-Ku, Sendai 980-8575, Japa

E-mail address: tyoshikawa@med.tohoku.ac.jp (T. Yos

http://dx.doi.org/10.1016/j.pharmthera.2017.04.0040163-7258/© 2017 Elsevier Inc. All rights reserved.

a b s t r a c t

a r t i c l e i n f o

Available online 27 April 2017

We previously reported on brain H1 receptor occupancy measurements of antihistamines in human brain using[11C]doxepin and positron emission tomography (PET). We proposed the use of brain H1 receptor occupancy toclassify antihistamines objectively into three categories of sedating, less-sedating, and non-sedating antihista-mines according to their sedative effects. Non-sedating antihistamines are recommended for the treatment of al-lergies such as pollinosis and atopic dermatitis because of their low penetration into the central nervous system.Physicians and pharmacists are responsible for fully educating patients about the risks of sedating antihistaminesfrompharmacological points of view. If a sedating antihistaminemust be prescribed, its sedative effects should bethoroughly considered before choosing the drug. Non-sedating antihistamines should be preferentially usedwhenever possible as most antihistamines are equally efficacious, while adverse effects of sedating antihista-mines can be serious. This review summarizes the pharmacological properties of clinically useful non-sedatingantihistamines from the perspective of histamine function in the CNS.

© 2017 Elsevier Inc. All rights reserved.

Keywords:HistamineNon-sedating antihistaminesPETHistamine H1 receptor occupancyCNSCarnosineHistidineSedationImpaired performanceP-glycoprotein

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1482. Histamine as a “good” substance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1493. Development of non-sedating antihistamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1504. PET evaluation of sedating action of antihistamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1515. P-glycoprotein inhibitors and multidrug-resistance genes (MDR) gene expression . . . . . . . . . . . . . . 1536. Clinical pharmacology of non-sedating antihistamines . . . . . . . . . . . . . . . . . . . . . . . . . . . 1547. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155Author disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

1. Introduction

Since histamine activity was discovered in 1910 by Sir Henry Dale, aNobel Prize winner in physiology or medicine 1936, a great number ofresearchers have investigated the physiological and pathological activi-ties of histamine. Furthermore, Daniel Bovet and Sir James W. Black,

gy, Tohoku University School ofn.hikawa).

who developed H1 and H2 receptor antagonists, received the NobelPrize in physiology ormedicine in 1957 and 1988, respectively, formak-ing a significant contribution to mankind. As part of recent progress inthe study of histamine, H3 and H4 receptors have been actively investi-gated (Brioni, Esbenshade, Garrison, Bitner, & Cowart, 2011; Passani &Blandina, 2011). To aid this research, genetic knockout mice havebeen created for H1–H4 receptors, histidine decarboxylase (HDC), andhistamineN-methyltransferase (HNMT). X-ray analysis of the H1 recep-tor has been also reported.While histaminewas considered detrimentalas an allergy-causing substance, recent studies have demonstrated that

Fig. 1. Carnosine–histidine–histamine pathway. The decarboxylation of L-histidine, one ofessential amino acids, is catalyzed by histidine decarboxylase (HDC), a pyridoxalphosphate-containing enzyme (3). The dipeptide, carnosine, is synthesized by carnosinesynthetase (2) and degraded by carnosinase (1). Histamine is an importantneurotransmitter in the eye of Dorsophila, and it is inactivated by carcinine synthetase(4), which converts to carcinine, a β-alanyl derivative (Chaturvedi, Luan, Guo, & Li,2016). Carcinine synthetase does not exist in humans, and the function of carcinine ispoorly understood at present in humans.

149K. Yanai et al. / Pharmacology & Therapeutics 178 (2017) 148–156

physiological activities of histamine are often beneficial to the humanbody. In the central nervous system, in particular, histamine plays animportant role in maintaining wakefulness and suppressing appetite.Accordingly, the guidelines for pollinosis, atopic dermatitis, and otherallergic disease now recommend non-sedating antihistamines withlesser penetrability into the central nervous system.

2. Histamine as a “good” substance

Histamine is a biogenic amine synthesized from the amino acid L-histidine by histidine decarboxylase (HDC). The various biological func-tions occur via four G protein–coupled receptor (GPCR) subtypes: H1 re-ceptor, H2 receptor, H3 receptor, and H4 receptor (Panula et al., 2015).The main histamine-producing cells are histaminergic neurons, thecell bodies of which lie in the hypothalamic tuberomammillary nucleus,gastric enterochromaffin-like (ECL) cells, mast cells, and basophils(Falus, Grossman, & Darvas, 2004). Gastric ECL cells release histamine

Fig. 2. Synthesis of carnosine in themuscle and its activities. Carnosine (β-alanyl-L-histidine) isthat is not a constituent of protein). When β-alanine is ingested, carnosine is synthesized in thechelating of intracellular Ca2+ and Cu2+, and (3) antioxidative action against reactive oxygen sactivate the histaminergic neuron system, which is very similar to histidine-induced actions.

upon stimulation by gastrin and acetylcholine. Through the effect of his-tamine on histamine H2 receptors, gastric acid is secreted from parietalcells. Mast cells and basophils store histamine within granules, and de-granulation occurs upon stimulation by an antigen in a sensitized state.Meanwhile, histamine contained in foods is also important. In relationto food-derived histamine, histamine food poisoning has long been rec-ognized in humans (Sarkadi, 2004; Visciano, Schirone, Tofalo, & Suzzi,2014). Upon proliferation of HDC-producing bacteria, considerableamounts of histamine may be synthesized from histidine contained infish. The symptoms of histamine food poisoning include urticaria, hypo-tension, nausea, vomiting, abdominal pain, diarrhea, headache, facialflush, and skin eruptions. The majority of symptoms develop withinone hour of eating. On the other hand, exogenously administered hista-mine is sometimes beneficial for us. Histamine itself has been approvedfor use in European countries and Israel to prevent relapse in acute my-eloid leukemia. In accordance with this, mice with histamine deficiencydue to genetic disruption of HDC showed a high rate of colon and skincarcinogenesis. The absence of histamine formation caused accumula-tion of immature myeloid cells, which was accompanied by an in-creased susceptibility to chemically induced cancer (Yang et al., 2011).

The amount of histidine contained in fishmeat is greater than that ofany other essential amino acid (http://wholefoodcatalog.info/). In theliving body, levels of carnosine, histidine, and histamine are consideredto be interactively and closely correlated (Fig. 1). Carnosine, an imidaz-ole dipeptide, has recently drawn attention for therapeutic potential instress- and age-related disorders (Babizhayev, 2014; Boldyrev, Aldini,& Derave, 2013; Cararo, Streck, Schuck, & Ferreira Gda, 2015; Hipkiss,2015). In addition to being synthesized from L-histidine by HDC, hista-minergic neurons, in particular, contain carnosinase, and histaminecan be efficiently synthesized from carnosine (Otani, Okumura, Nagai,& Okumura, 2008). During exercise, carnosine is synthesized from histi-dine and β-alanine in muscle (Blancquaert, Everaert, & Derave, 2015;Hoffman, Stout, Harris, & Moran, 2015). It has been proposed thatafter being released frommuscle, carnosine can stimulate central hista-minergic neurons as shown in Fig. 2. Exercise is very effective inpreventing dementia, as demonstrated by a number of epidemiolog-ical studies; however, the molecular mechanism underlying thisphenomenon is unknown. Carnosine is efficiently incorporated intohistamine neurons in the brain and reported to reduce the cytotoxic-ity owing to amyloid β protein and suppresses its deposition (Coronaet al., 2011). The activities of carnosine and histidine, both of whichhave the same imidazole skeleton, are as follows: antioxidant,metal chelating (Ca2+, Zn2+, and Cu2+) inside and outside the cell,pH buffering activity (Boldyrev et al., 2013; Swietach, Leem,Spitzer, & Vaughan-Jones, 2014), and histamine neuron-activatingeffects (Shen et al., 2007).

a dipeptide produced inmuscle by condensation of histidine and β-alanine (an amino acidmuscle (Blancquaert et al., 2015), and (1) buffering of intracellular H+ in muscle, (2 & 4)pecies (ROS) occur. Carnosine can be released frommuscle into the circulation, and it can

Fig. 3. Differences in pharmacological actions on histamine-induced skin dye leakagebetween bepotastine optical isomers. The data show the mean ± SEM of leaked dyeintensity in 5 rats (Narita et al., 1997). Oral formulations of (S)bepotastine have beenapproved by the Japanese regulatory agency in July 2000, and (S)bepotastine was alsoreformulated for its topical use in the treatment of allergic conjunctivitis in the USA.Treatment of allergic conjunctivitis with non-sedating (S)bepotastine ophthalmicsolution is one of effective anti-allergic medications that provides rapid and sustainedreduction of ocular itching and other allergy-associated ocular symptoms (Bergmann,Williams, & Gomes, 2014).

150 K. Yanai et al. / Pharmacology & Therapeutics 178 (2017) 148–156

The central histaminergic neuron system, with cell bodies located inthe hypothalamus, constitutes one of the neuronal monoaminergic sys-tems (Haas & Panula, 2003; Haas, Sergeeva, & Selbach, 2008;Watanabe&Wada, 1991). Their neural fibers are extensively distributed through-out the brain and part of the spinal cord. These neurons are strongly ex-cited in the awakening state and release histamine. Histamine thenintensely promotes cerebral cortex function directly via H1 and H2 re-ceptors, excitation of cholinergic and noradrenergic neurons in thebrain stem, cholinergic neurons in the substantia innominate, andglutaminergic neurons in the thalamus. Cerebrocortical activation byhistamine is very high and closely related to maintenance of wakeful-ness (Shan, Dauvilliers, & Siegel, 2015), promotion of cognitive function,and suppression of appetite and stress (Watanabe & Yanai, 2001).Therefore, when a highly brain-penetrable first-generation antihista-mine is administered, the level of wakefulness drops, learning/memorylevels fall, and body weight increases owing to cerebrocortical inhibi-tion (Yanai & Tashiro, 2007). Pharmacoepidemiological studies have re-ported that first-generation antihistamine drugs increase the incidenceof dementia (Gray et al., 2015). There are several lines of evidence thatbrain histamine is implicated in Alzheimer's disease. For example, bothof the brain HDC and the histidine concentration in cerebrospinal fluidwere decreased significantly in Alzheimer disease (Fonteh, Harrington,Tsai, Liao, & Harrington, 2007; Schneider et al., 1997). In addition, sever-al N-methyl-D-aspartate (NMDA)-receptor antagonists includingmemantine, which is often used for the treatment of Alzheimer's dis-ease, enhanced histamine neuron activity in rodents (Motawaj,Burban, Davenas, & Arrang, 2011). A possible beneficial effect of hista-mine-related drugs on Alzheimer's disease might not be solely due toa simple symptomatic relief of cognitive symptoms, but could also bethe consequence of disease modifying actions (Zlomuzica et al., 2016).From this perspective, non-sedating antihistamines are clinically supe-rior, as central histamine activities are not suppressed (Church et al.,2010; Holgate et al., 2003; Yanai et al., 2011).

3. Development of non-sedating antihistamines

Antihistamines have been used for treating allergy since the 1940s(Simons & Simons, 2011). The first antihistamine that is toxic to humanswas synthesized in 1937 by Italian pharmacologists Daniel Bovet andAnne-Marie Staub. Pyrilamine, which was discovered after screening anumber of compounds, was first administered to humans in 1944. Eventoday, pyrilamine (also named mepyramine) is used in basic research asa standard H1 antagonist. First-generation antihistamines such aspyrilamine and promethazine became prototypes for many central ner-vous system drugs such as antipsychotics and antidepressants. In fact,someantidepressants andantipsychotic drugs are among themost potentH1 antagonists (Kanba & Richelson, 1991; Sato et al., 2013, 2015).

While the classical first-generation antihistamines were effectiveagainst allergic disease, they had the drawback of a strong sedating ef-fect due to their passage through the blood–brain barrier. Sedative ad-verse reactions include drowsiness (emotional experience) andimpaired performance (emotional expression). Further, due to poor se-lectivity for H1 receptors, the incidence of anticholinergic adverse reac-tions such as dry mouth, anuresis, and tachycardia is high (Simons &Simons, 2011; Yanai, 2012). Therefore, the utility of the first-generationsedating antihistamines for allergic disease is limited. Aiming to over-come these major defects, the second-generation antihistamines weredeveloped with high H1 receptor selectivity, low brain penetrability,and long plasma half-life. Due to the introduction of a hydrophilic func-tional group (\\COOH or\\NH2), the second-generation non-sedatingantihistamines are less likely to pass the blood-brain barrier, andcause a lower incidence of sedation (Yanai et al., 2011). In particular,the introduction of the COOH group is important for the non-sedatingproperties of antihistamines because this gives rise to so-called zwitter-ionic” compounds, positive and negative charges in the same molecule,which can explain poor BBB penetration.

First-generation antihistamines including mepyramine, hydroxizine,diphenhydramine, chlorpheniramine, and promethazinewere developedbetween the 1940s and 1970s. Between 1980 and 1990, astemizole,terfenadine, loratadine, epinastine, olopatadine, and ebastinewere devel-oped as parent compounds for the second-generation antihistamines.However, astemizole and terfenadine had an ECG QT-prolonging actionthrough the blockade of HERG1 K+ channels, inducing severe arrhyth-mias on rare occasions, and these were removed from the market(Leurs, Church, & Taglialatela, 2002). The major metabolites of the sec-ond-generation antihistamine parent compounds such as loratadine andterfenadine are safe and efficacious with neither cardiotoxicity nor CNSeffects, and are therefore used desloratadine and fexofenadine, respec-tively, as non-sedating antihistamines.

After 2000, levocetirizine and bepotastine were developed byisolating optical isomers from the second-generation antihistamines.(S)-Bepotastine and (R)-levocetirizine are carboxyl group-containingnon-sedating antihistamines, and the optical isomers with three-dimensional structures and stronger binding affinity (potency) areused for clinical purposes (Gillard, Van Der Perren, Moguilevsky,Massingham,& Chatelain, 2002). Fig. 3 shows the difference in the effectof (S)-bepotastine and (R)-bepotastine on histamine-induced skin dyeleakage (Narita et al., 1997; Ueno, Inagaki, Nagai, & Koda, 1998).Pharmacologically speaking, it is desirable to develop a drug that doesnot contain optical isomers of different potencies.

Fig. 4. Carboxyl group-containing zwitterionic (A) and amino group-containing non-zwitterionic (B) antihistamines. * indicates asymmetric carbon related to opticalisomerism. # indicates a double bond relevant to a cis-trans isomer, which is not anoptical isomer, but a geometric isomer with a different three-dimensional structure. $indicates a prodrug that is converted to its active metabolite in the body.

Fig. 5. Interactions of bilastine and fexofenadine with the H1 ligand-binding pocket. Docking siCHARMm force field (Dassault Systèmes, Cedex, France). Crystal structure of doxepin-H1 recepused as a template structure. (A) Predicted binding mode of bilastine with H1 receptor. Bilastinnitrogens blue. H1 receptor (green) and selected residues are shown as ribbon model and sSuperposition of bilastine (pink) and fexofenadine (cyan) in the active site. (C) Chemical struand (C) show corresponding parts of each compound. Bilastine and fexofenadine are assumedin this figure legend, the reader is referred to the web version of this article.)

151K. Yanai et al. / Pharmacology & Therapeutics 178 (2017) 148–156

Fig. 4 shows clinically used carboxyl group-containing and aminogroup-containing non-sedating antihistamines, which are also consid-ered as zwitterionic and non-zwitterionic antihistamines, respectively.The second-generation antihistamines have stronger anti-inflammatoryactions, while clinical efficacy is almost equal between the first-genera-tion and second-generation antihistamines. In addition, cardiovascularadverse reactions, anticholinergic activity, and sedative properties arerarely observed with the major carboxyl-containing second-generationmetabolites. Amino group-containing compounds such as mequitazine,epinastine, and desloratadine have lower specificity for H1 receptorsand may block other receptors (e.g., muscarinic receptors). Ebastineand loratadine are prodrugs that become active in the body throughconversion to carboxyl group-containing (carebastine) and aminogroup-containing compounds (desloratadine), respectively.

Carboxyl group-containing antihistamines are zwitterionic, contain-ing N+ and COO−, and exhibit high specificity for H1 receptors.Shimamura et al. (2011) recently reported the crystal structure ofhuman histamine H1 receptor complex with doxepin and bindingmodels of zwitterionic non-sedating antihistamines. The H1 receptorstructure significantly improved understanding of high H1 receptor se-lectivity of carboxyl group-containing antihistamines. Fig. 5 shows thebinding modes of bilastine and fexofenadine with H1 receptor bydocking simulation (unpublished data). A docking model of bilastine-H1 receptor complex was obtained by energy minimization in thesame manner as for fexofenadine using the initial model based on theassumption that bilastine and fexofenadine have the commonpharmacophore. These results show bilastine and fexofenadine are as-sumed to bind in a similar mode to H1 receptor.

In general, the brain penetration depends on the concentration gra-dient, hydrophilic properties,molecular size, and charge, if themoleculehas a net charge at physiological pH. Other determining factors of non-sedating antihistamines include P-glycoprotein, cytochrome P450 en-zymes, enantiomers and pKa (acid dissociation constant). In particular,non-sedating antihistamines have a high affinity for P-glycoprotein,while the classical antihistamines are not the substrates (Hu, Sieck, &Hsu, 2015). Multiple factors may contribute to the penetration throughblood-brain barrier.

4. PET evaluation of sedating action of antihistamines

First- and second-generation antihistamines are generally classifiedinto sedating and non-sedating compounds based on the presence/ab-sence of sedation. Sedating action is usually evaluated on the basis ofsubjective drowsiness and impaired performance, as measured by a

mulation of bilastine-H1 receptor complex was performed by Discovery Studio 2016 withtor complex from Protein data bank accession number 3RZE (Shimamura et al., 2011) wase is shown as ball and stick model with carbon atoms colored magenta, oxygens red, andtick models, respectively. Hydrogen bonds are represented by thin lines (yellow). (B)ctures and pharmacophore model of bilastine and fexofenadine. Roman numbers in (B)to bind in the similar mode to H1 receptor. (For interpretation of the references to color

152 K. Yanai et al. / Pharmacology & Therapeutics 178 (2017) 148–156

cognitive function test. We have devised a method to non-invasivelyquantify brain H1 receptor density, using [11C]doxepin and PET. Usingthis method, we evaluated the sedating action of antihistamines bymeasuring cerebral histamine H1 receptor occupancy after single-doseadministration of antihistamine (Yanai et al., 2016). After placebo/anti-histamine is taken by healthy young males (20–30 years old), [11C]doxepin is administered at Tmax, and cerebral H1 receptor occupancy ismeasured. More than one week later, the second [11C] doxepin PETscan is performed after the administration antihistamine/placebo inthe same subject. There are gender differences between males and fe-males in cerebral H1 receptor findings on PET (Yoshizawa et al., 2009)as shown in Fig. 6. In addition, H1 receptor bindingmarkedly decreasedwith age (Higuchi et al., 2000). Therefore, the sample population wasrestricted to healthy young males in our PET studies.

Cerebral H1 receptor occupancy was at least 50% after single-doseadministration of a first-generation antihistamine, with a high inci-dence of drowsiness and impaired performance (Okamura et al.,

Fig. 6.Gender difference in H1 receptors in the human brain. Twelve healthy normal female volnormalmale volunteers (age 21.8±1.2,weight 62.0±4.8 kg, BMI 20.6±1.8;mean±SD)weremale (B) subjects are illustrated as the binding potential (Bmax/Kd) of H1 receptors. Female scerebral cortical areas than male volunteers. Sexual dimorphism on brain histamine system wFerretti, 1999).

2000). In contrast, the occupancy ratewas around 20% or below for sec-ond-generation antihistamines (Fig. 7).We classified the sedating effectof antihistamines, based on cerebral H1 receptor occupancy after single-dose administration, into sedating (≥50%), less sedating (50–20%), andnon-sedating (b20%) groups. As for the relationship between cerebralH1 receptor occupancy and drowsiness/impaired performance, im-paired performance was more frequently observed with statistical sig-nificance when cerebral H1 receptor occupancy was 20% or higher. Inthe case of a completely non-sedating antihistamine such asfexofenadine, H1 receptor occupancy did not increase with a higherdose of the drug. In fact, fexofenadine and bilastine do not penetratethe BBB at all and, consequently, have no H1 receptor occupancy(Farré et al., 2014; Hiraoka et al., 2015).

It is known that the sedating effect of antihistamines varies amongindividuals. As H1 receptor genetic polymorphism does not frequentlyoccur, it is difficult to explain the inter-individual difference in drowsi-ness by polymorphism. Therefore, inter-individual differences could

unteers (age 22.3± 2.5, weight 50.3± 3.7 kg, BMI 20.3± 1.7; mean± SD) and 12 healthyexaminedusing [11C]doxepin. The averaged and normalized PET images in female (A) andubjects have significantly higher binding potential of [11C]doxepin to H1 receptors in theas reported previously in animal studies (Ferretti et al., 1998; Ghi, Orsetti, Gamalero, &

153K. Yanai et al. / Pharmacology & Therapeutics 178 (2017) 148–156

be explained in terms of H1 receptor occupancy or differences/changesin sensitivity to subjective experiences. In order to decrease the report-ed bias, all published reports onplacebo-controlled randomized double-blind studies of drowsiness and impaired performance induced by anti-histamines were precisely analyzed by research groups of University ofSurrey (Hindmarch, 2009; McDonald, Trick, & Boyle, 2008; Shamsi &Hindmarch, 2000). They then proposed the incidence of sedation scoredas proportional impairment ratio (PIR) for each antihistamine from sub-jective and objective perspectives. PIR was mostly correlated to H1 re-ceptor occupancy rate on PET (The inset in Fig. 7). Both values ofcerebral H1 receptor occupancy and PIR were sequential without anyclear non-sedating cutoff values.

Considering the increase in allergy patients, appropriate use of fast-acting antihistamines is important. However, sufficient consensus hasnot yet been reached on the characteristics of ideal antihistamines.CONGA(ConsensusGroupofNewGeneration of Antihistamines), an ex-pert committee, was launched to examine the subject, and criteria forideal antihistamines were proposed (Holgate et al., 2003). Classificationof sedating actions based on H1 receptor occupancy was adopted. In theatopic dermatitis treatment guideline recently issued by the JapaneseDermatological Association, standards for “non-sedating antihista-mines” were established for the first time in Japan, and classificationbased on H1 receptor occupancy was introduced. Even in cases whereimpaired performance is definitely observed, the patient is often notconscious of drowsiness. Therefore, the sedating action of antihista-mines should be assessed by cerebral H1 receptor occupancy on PET,rather than by subjective drowsiness or difficult-to-detect impairedperformance (Hindmarch, 2009).

Our doxepin-PET study demonstrated that about 50% of cerebral H1

receptors were occupied even 12 h after the use of a sedatingantihistamine at night (Zhang et al., 2010), and that about 50% of cere-bral H1 receptorswere occupied even after the use of sedating antihista-mine-containing eye drops (Yanai et al., 2016). The cerebral half-life ofsedating antihistamines such as diphenhydramine is at least 30 h,whichis much longer than plasma half-life (Yanai et al., 2016). In fact, when asedating antihistamine is used as a sleep inducer at night, theremay be arisk of medication hangover the next day (Church et al., 2010).

Fig. 7.Classification of antihistamines byH1 receptor occupancy and sedating actions after singleantihistamine administration using [11C] doxepin-PET by our and other research groups. Theimpaired performance was not observed in a simultaneously performed cognitive function teas “non-sedating.” As shown in the inset right, the incidence of sedation (PIR) obtained by aThe lower H1 receptor occupancy, the lower was PIR.

Furthermore, topical administration of sedating antihistamines to theeye or nasal mucosa results in a great number of cerebral H1 receptorsbeing occupied due to the absence of a first-pass effect. Therefore,non-sedating antihistamine-containing eye or nasal drops should beused as first choice treatments.

We propose a method to assess sedating action bymeasuring H1 re-ceptor occupancy after single-dose administration. Theweakness of thismethod is that the measurement is not made in allergy patients aftermultiple dosing. In order to carry out PET measurement twice, multipledosingneeds to be conducted in the same subjects,which is not a simpleprocedure. A study has actually been carried out tomeasure H1 receptoroccupancy in patients with mild allergy after single and consecutivedosing with the non-sedative antihistamine olopatadine (Senda et al.,2009). The finding was that receptor occupancy after consecutive dos-ing (about 45%) was higher than the level after single-dose administra-tion (about 15%). H1 receptor occupancy may possibly increase whenrepeatedly administering somedrugs classified as non-sedating antihis-tamines. H1 receptor occupancy should be measured and compared be-tween single and consecutive dosing for fexofenadine or bilastine,completely non-sedating antihistamines exhibiting almost noH1 recep-tor occupancy.

5. P-glycoprotein inhibitors and multidrug-resistance genes (MDR)gene expression

One possible explanation for non-sedative properties is theefflux function of p-glycoprotein through blood-brain barrier. Ahuman study using functional MRI and cognitive studies showedincreased sedation during the combination cetirizine and verapamil(Conen et al., 2013). In our preliminary study, we examined the influ-ence of p-glycoprotein on non-sedating antihistamines in mice andhumans using different methods (Fig. 8). As cetirizine is a racemic mix-ture of levocetirizine and dextrocetirizine, we examined the brain toblood ratio of [11C]verapamil as an index of substrate of P-glycoproteinafter treatment of levocetirizine and dextrocetirizine (Iida et al., 2012;Ishiwata, Kawamura, Yanai, & Hendrikse, 2007). Both isomers did nothave any significant effects on the uptake [11C]verapamil in the mouse

-dose administration. This is a summaryofmeasurements of H1 receptor occupancies afterdata are represented as the mean ± SD. When H1 receptor occupancy was 20% or lower,st (Okamura et al., 2000; Tashiro et al., 2004), and therefore, the drug could be classifiedliterature search (McDonald et al., 2008) is well-correlated with H1 receptor occupancy.

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brain (Fig. 8A). In contrast, cyclosporine A, a strong inhibitor of p-glyco-protein, significantly increased the uptake [11C]verapamil in the mousebrain. As species difference has been observed as a substrate of P-glyco-protein (Wang, Casciano, Clement, & Johnson, 2001), further studies arewarranted to clarify the actual role of p-glycoprotein inhibitors on thebrain penetration of non-sedating antihistamines in humans.

The efflux of fexofenadine by P-glycoprotein is not as remarkable asloratadine and cetirizine (Obradovic, Dobson, Shingaki, Kungu, &Hidalgo, 2007), even though theH1 receptor occupancy of fexofenadineis nearly zero in humans. A previous report suggested that the high pKaof fexofenadine played an important role in themembrane permeability(Kikuchi, Nozawa,Wakasawa,Maeda, & Tamai, 2006). The high concen-tration of ionized form of fexofenadine at physiological pHmight inhibitthe brain penetration in humans. The plasma concentrations offexofenadine after a single oral administration were lower in personswith 2677AA/3435CC genotype of MDR1 than in personswith other ge-notypes (Yi et al., 2004). In contrast, the function of P-glycoprotein atthe blood-brain barrier measured by the brain uptake of [11C]verapamilwas not different between the haplotypes of 3 single nucleotide poly-morphisms (C1236T, G2677T, and C3435T) of MDR1 gene (Takano etal., 2006). We also did not observe any significant correlation of a poly-morphism in C3435T of MDR-1 with the H1 receptor occupancy byfexofenadine (unpublished data), although a tendency of lower brainpenetration of fexofenadine exists in persons with 3435CC genotype(Fig. 8B). These studies suggested the MDR gene expression might nothave any considerable effects on the H1 receptor occupancy in humans.

6. Clinical pharmacology of non-sedating antihistamines

6.1. Constitutive activity

Many international guidelines recommend non-sedating antihista-mines as the first choice for treating allergic diseases (Magerl et al.,2016; Zuberbier et al., 2006, 2014). While GPCR-mediated signal trans-missionwas originally considered to be possible only after agonist bind-ing, recent findings suggest that H1 receptor responses can betransmitted when a great number of histamine H1 receptors areexpressed, even in the absence of the agonist histamine. Such a stateof histamine receptor activation in the absence of histamine is calledconstitutive activity. Antihistamines act as inverse agonists on constitu-tively active H1 receptors, rendering activated histamine H1 receptorsinactive (Leurs et al., 2002; Monczor, Fernandez, Fitzsimons, Shayo, &Davio, 2013). In allergic individuals, allergic responses are transmitted

Fig. 8. Effects of p-glycoprotein on the brain penetration of non-sedating antihistamines in manalyzed using [11C]verapamil in vivo (A). Levocetirizine (10 mg/kg, PO), dextrocetirizine (1(each group = 6–8) before the intravenous injection of [11C]verapamil, a substrate of p-glycomeasured. One-way ANOVA Dunnett's multiple comparison shows insignificant effects of levohas significant effects as a positive control vs. saline and cetirizine groups (P b 0.01). (B) Wedetermined after orally administered fexofenadine (Tashiro et al., 2004). Insignificant correlaby fexofenadine was observed. The data are represented as the mean ± SD.

even without histamine release from mast cells, and therefore, treat-ment with antihistamines is initiated before the pollinosis season be-gins. This is with the aim of suppressing allergic activity, presumablynot by directly blocking histamine activity, but by restraining constitu-tive activity. From this perspective, long-term use of non-sedating anti-histamines in monthly regimens is desirable as adverse reactions areuncommon (Grob, Auquier, Dreyfus, & Ortonne, 2009). Carboxylgroup-containing non-sedating antihistamines are particularly suitablefor long-term use due to their reduced anticholinergic activity.

6.2. Potency and efficacy

Binding affinity (potency) to H1 receptors is substantially differentamong antihistamines (Yanai et al., 2011).More than a hundredfold dif-ference exists in binding affinity (potency) among various antihista-mines. Based on potency, non-sedating antihistamines can beclassified into low- (loratadine, fexofenadine) and high-potency groups(bepotastine, olopatadine, cetirizine, epinastine, levocetirizine). How-ever, though potency varies greatly among antihistamines, clinical effi-cacy as represented by maximum responsiveness is the same ifadministered in sufficient dosages. For this reason, it is desirable to in-crease the dosage of carboxyl group-containing non-sedating antihista-mines if efficacy is insufficient. As the pharmacokinetics of non-sedatingantihistamines are very different among individuals, a fixed dosagemaynot produce the specified efficacy. The latest guidelines recommendthat the dosage of non-sedating antihistamines can be increased by 2–4 times when efficacy is insufficient (Zuberbier et al., 2006, 2014). Car-boxyl group-containing non-sedating antihistamines with no anticho-linergic action are suitable for dose increases.

6.3. Pediatric use

Caution is advised in administering sedating antihistamines for chil-dren. The incidence of sedative effects is even higher in children, andtheir learning ability may be reduced. As estimated from animal exper-imental data, administration of sedating antihistamines is likely to in-duce convulsions in children with a convulsive predisposition. Theyalso increase the risk of obesity through central H1 receptor blockade(Kim, Huang, Snowman, Teuscher, & Snyder, 2007; Masaki &Yoshimatsu, 2006). In a small-scale observational study in children, fe-brile convulsion worsened with the use of a sedating antihistamine(Zolaly, 2012). The regulatory agency advised the discontinuation ofOTC cold medicines containing sedating antihistamines for children

ice (A) and humans (B). Brain penetration of non-sedating antihistamines in mice were0 mg/kg, PO), cyclosporine A (CsA)(50 mg/kg, IV) and saline were administered to miceprotein. At 15 min, the mice were sacrificed and the radioactivity of brain and blood was- and dextro-cetirizine on [11C]verapamil penetration in vivo. In contrast, cyclosporine Aanalyzed the MDR-1 sequence in 24 volunteers whose H1 receptor occupancy had beention of a polymorphism in exon 26 (C3435T) of MDR-1 with the H1 receptor occupancy

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under 2 years of age. Accordingly, pharmaceutical companies have vol-untarily recalled such medicines. After a voluntary market withdrawaland labeling revision, emergency department visits for adverse drugevents due to cough and cold medicine declined among children agedb2 years and 2 to 3 years (Hampton, Nguyen, Edwards, & Budnitz,2013; Shehab, Schaefer, Kegler, & Budnitz, 2010). As the efficacy ofnon-sedating antihistamines has proven in pediatric allergic diseases(Warner, 2001), non-sedating antihistamines should also be the firstchoice for pediatric allergy.

7. Conclusion

The release of histamine and its many effects on target cells contrib-utes to the acute and chronic symptomatology characteristic of allergydisorders. Blockade of this receptor provides a highly successful ap-proach to controlling allergic symptoms. The second-generation anti-histamines can be so called “non-sedating antihistamines” because ofthe lack of penetration through the blood–brain barrier. The pharmaco-logical properties of clinically useful non-sedating antihistamines aredescribed in detail in terms of the recent advance of histamine research.

Author disclosure

The authors (Drs. Tashiro M and Yanai K) received research grantsfrom GlaxoSmithKline Japan, on PET and cognitive human studies onlevocetirizine. In the last 3 years, Yanai K had received lecture honorariafrom manufactures of 2nd generation antihistamines, including Sanofi,GlaxoSmithKline, Kyowa-Kirin, Taiho and Mitsubishi Tanabe Pharma-ceutical Co. Ltd. Other authors have no conflict of interest. Decisions re-garding all aspects of the review were made by all authors withoutconsulting with pharmaceutical companies.

Acknowledgments

This work was supported in part by Grants-in-Aid for Scientific Re-search (#26253016 and #26670117) from the Japan Society for Promo-tion of Science (JSPS). We appreciate Dr. Takashi Watanabe (ChiefResearcher, Medicinal Chemistry Laboratory, Pharmaceutical ResearchCenter, Meiji Seika Pharma Co., Ltd.) for discussing the manuscript onthe model simulation between H1 receptor and non-sedatingantihistamines.

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Visciano, P., Schirone, M., Tofalo, R., & Suzzi, G. (2014). Histamine poisoning and controlmeasures in fish and fishery products. Frontiers in Microbiology 5, 500.

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Warner, J. O. (2001). ETAC Study Group. Early treatment of the atopic child. A double-blinded, randomized, placebo-controlled trial of cetirizine in preventing the onsetof asthma in children with atopic dermatitis: 18 months' treatment and 18 months'posttreatment follow-up. The Journal of Allergy and Clinical Immunology 108, 929–937.

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H1-Antihistaminika:

Pharmakologische Grundlagender WirkungANDREAS DIT TMANN | KLAUS MOHR

Histamin: Bildung und AbbauHistamin-freisetzende Zellen bilden das biogene Amin ausder Aminosäure Histidin unter Katalyse durch eine L-Histi-din-Decarboxylase (Abb. 1). Intrazellulär kann Histamin vesi-kulär gespeichert werden. Nach seiner Freisetzung wirktes in der protonierten Form auf die Rezeptoren ein. Inak-tiviert wird es durch zelluläre Aufnahme, wahrscheinlich

Histamin wird als lokaler Botenstoff von verschiedenen Zellengebildet und freigesetzt. Es vermittelt seine Wirkungen überHistamin-Rezeptoren, von denen zur Zeit vier Subtypen, H1 – H4, bekannt sind. Antagonisten an H1-Rezeptoren dienenzu verschiedenen therapeutischen Zwecken, wobei ihre Fähigkeit zur Überwindung der Blut-Hirn-Schranke den Ver-wendungszweck maßgeblich bestimmt.

vermittelt über membranale Transportmoleküle, und an-schließenden Abbau. Der Hauptabbauweg wird intrazellulärdurch das Enzym Histamin-N-Methyltransferase eingeleitetund führt zu Ntele-Methylhistamin. Dieses wird unter Mit-wirkung der Monoaminoxidase in zwei weiteren Schrittenzum Endprodukt Ntele-Methylimidazolylessigsäure oxidativdesaminiert. Die Desaminierung durch eine Diaminoxida-se (Histaminase) spielt im Allgemeinen quantitativ eine ge-ringere Rolle; im ZNS wird sie gar nicht beobachtet. EineRückaufnahme durch die freisetzende Zelle mit Wieder-verwertung, wie es z.B. bei Noradrenalin und Serotoninvorkommt, gibt es bei Histamin nicht.

Histamin: Quellen, Rezeptoren, Wirkungen Histamin dient als ein lokaler Botenstoff der Entzündung,als parakriner Stimulus der Magensäuresekretion und alsnervale Überträgersubstanz (Abb. 2). Es sind zur Zeit 4 Sub-typen der Histaminrezeptoren bekannt, die alle in die Fa-milie der G-Protein gekoppelten Rezeptoren gehören.

EntzündungDie Freisetzung von Histamin aus Mastzellen und basophi-len Granulozyten kann durch Allergene oder durch so ge-nannte Histaminliberatoren hervorgerufen werden (Abb.2). Vor allem bei allergischen Reaktionen werden neben Hi-stamin auch zahlreiche andere Mediatoren ausgeschüttet.Bei der allergischen Reaktion vom Typ-I, die auch als ana-phylaktische Sofortreaktion bezeichnet wird, sind es biva-lente Antigene, die zellfixierte IgE-Antikörper brückenartigmiteinander verbinden. Dies bewirkt eine intrazelluläreCa2+-Mobilisierung, die zur Exozytose der Speichergranulaund zur Freisetzung des Histamins führt. Im betroffenenGewebe ruft Histamin verschiedene Effekte hervor, an de-nen unterschiedliche Histaminrezeptoren beteiligt sind(Abb. 3). Dies wird unten genauer betrachtet.

Eine nicht über IgE-vermittelte Histaminfreisetzungkann durch Arzneistoffe ausgelöst werden, z.B. durch Mor-phin und einige Röntgenkontrastmittel, sowie durch Fak-toren der Komplementkaskade, die eine Rolle in der un-spezifischen Immunabwehr spielt.

Magensäure-SekretionHistamin wird von den enterochromaffin-artigen Zellen derMagenschleimhaut freigesetzt (enterochromaffin-like cells,

HN

NNH2

Histidin

Histamin

Decarboxylase

N-MethyltransferaseMonoaminoxidase B

H3CN

N

COOH

A B B . 1 | H I S TA M I N : B I L D U N G U N D A B BAU

Histamin-freisetzende Zellen bilden das biogene Amin aus der Aminosäure Histidinunter Katalyse durch eine L-Histidin-Decarboxylase. Nach seiner Freisetzung wirktHistamin auf die Rezeptoren der Zielzelle ein. Der Hauptabbauweg wird intrazel-lulär durch das Enzym Histamin-N-Methyltransferase eingeleitet und führt zu Ntele-Methylhistamin, das dann unter Mitwirkung der Monoaminoxidase in zwei weite-ren Schritten zum Endprodukt Ntele-Methylimidazolylessigsäure oxidativ desami-niert wird.

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ECL-Zellen; Abb. 2). Diese sind nicht zu verwechseln mitden enterochromaffinen Zellen der Dünndarmschleimhaut,die Serotonin abgeben. Die ECL-Zellen besitzen Rezepto-ren für das Hormon Gastrin und das von vagalen Nerven-endigungen freigesetzte Acetylcholin, welche die Histamin-freisetzung fördern. An den benachbarten Belegzellen regtHistamin über H2-Rezeptoren die Salzsäureproduktion an.

NeurotransmissionAus Nervenendigungen in bestimmten Hirngebieten freige-setztes Histamin vermag über H1-Rezeptoren Wachheit so-wie Übelkeit und Erbrechen zu fördern. Außerdem hemmtdas im synaptischen Spalt befindliche Histamin im Sinne ei-ner negativen Rückkopplung die weitere Histamin-Abgabeaus dem freisetzenden Neuron. Dieser autoinhibitorische Effekt wird über präsynaptische H3-Rezeptoren vermittelt.Auch Neurone, die andere Überträgerstoffe freisetzen, kön-nen auf ihrem Nervenende H3-Rezeptoren tragen und so ei-nem heteroinhibitorischen Effekt von Histamin unterliegen.Es sei angemerkt, dass das Prinzip der H3-Rezeptor-vermit-telten Autoinhibition auch bei nicht neuronalen Quellenvon Histamin verwirklicht zu sein scheint, so bei den His-tamin-produzierenden ECL-Zellen [1].

Histamin und AtopieDer Begriff Atopie bezeichnet eine vererbbare, IgE-ver-mittelte Überempfindlichkeit gegen Umweltstoffe undmöglicherweise auch endogene Substanzen. Atopische Er-krankungen sind die allergische Rhinokonjunktivitis, dasatopische Ekzem (Synonyma: endogenes Ekzem, Neuro-dermitis, atopische Dermatitis) und das allergische Asthmabronchiale. Histamin, das neben anderen Mediatorsub-stanzen aus Mastzellen und basophilen Granulozyten frei-gesetzt wird, vermittelt dabei viele seiner Wirkungen nichtnur über H1-Rezeptoren (Abb. 3). So kann die Gefäßerwei-terung in den Arteriolen indirekt über H1- und direkt überH2-Rezeptoren ausgelöst werden: H1-Rezeptoren in der Zell-membran der Gefäßendothelzellen induzieren die Abgabevon Stickstoffmonoxid, das die glatten Gefäßmuskelzellender Arteriolen erschlaffen lässt; direkt kann der Gefäßto-nus durch Erregung von H2-Rezeptoren der Gefäßmuskel-zellen vermindert werden. Dies erklärt, weshalb bei ana-phylaktischen Kreislaufreaktionen auch H2-Antihistaminikaeingesetzt werden. Am venösen Ende des Kapillarbettes, inden Venolen, vermitteln H1-Rezeptoren ein Zusammen-ziehen der Endothelzellen; die entstehenden Lücken erlau-ben den Ausstrom von Plasmaflüssigkeit. Zum Ort der His-tamin-Freisetzung können über den Prozess der Chemota-xis andere Entzündungszellen angelockt werden. So scheintHistamin über H4-Rezeptoren die Einwanderung von eosi-nophilen Granulozyten fördern zu können, die charak-teristisch für atopische Entzündungen sind.

Der H4-Subtyp der Histaminrezeptoren wurde erst vorwenigen Jahren entdeckt [2-4]. Offenbar kommt er vor-wiegend (oder gar ausschließlich) in der Peripherie vor, imGegensatz zum H3-Rezeptor, der hauptsächlich im ZNS

Antigen

IgE

Mastzelle

Histaminliberatoren:Arzneistoffe

Komplementfaktoren

Histaminund andere

Mediatorsubstanzen

ECL-Zelle

Gastrin

N. vagus

HistaminH2

H+ Cl–

Belegzelle

H3

Histamin

H1: Wachheit Nausea

H3

andererTransmitter

A

B

C

A B B . 2 | H I S TA M I N : Q U E L L E N , R E Z E P TO R E N , W I R KU N G E N

Die Freisetzung von Histamin aus Mastzellen und basophilen Granulozyten kanndurch Allergene oder durch so genannte Histaminliberatoren hervorgerufen wer-den (A). Histamin wird von den enterochromaffin-artigen Zellen der Magenschleim-haut z.B. nach einer Stimulation durch Gastrin oder durch das von vagalen Nerven-endigungen freigesetzte Acetylcholin freigesetzt (enterochromaffin-like cells, ECL-Zellen). An den benachbarten Belegzellen regt Histamin über H2-Rezeptoren dieSalzsäureproduktion an (B). Aus Nervenendigungen in bestimmten Hirngebietenfreigesetztes Histamin kann über H1-Rezeptoren Wachheit sowie Übelkeit und Er-brechen fördern. Über eine H3-Rezeptor-vermittelte negative Rückkopplung hemmtdas freigesetzte Histamin die weitere Histamin-Abgabe aus dem Neuron. Auch Neu-rone, die andere Überträgerstoffe freisetzen, können auf diesem Weg inhibiertwerden (C).

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lokalisiert ist. Weitere H1-Rezeptor-vermittelte Wirkungensind in Abb. 3 aufgeführt.

H1-AntihistaminikaZielstruktur-Selektivität

Im Gegensatz zu den Histaminrezeptor-Antagonisten spie-len Agonisten bisher keine therapeutische Rolle. Die H1-und H2-Antihistaminika weisen eine erstaunliche Selekti-vität innerhalb der Histaminrezeptorfamilie für die Beset-zung des jeweiligen Rezeptorsubtyps auf. Bemerkenswertist, dass die älteren H1-Antihistaminika dabei durchaus einetherapeutisch relevante Affinität zu anderen Neurotrans-mitterrezeptoren besitzen – in dieser Hinsicht also nicht se-lektiv sind. So blockiert das Antihistaminikum Promethazinneben den H1-Rezeptoren auch beispielsweise muskarini-sche Acetylcholinrezeptoren und Dopaminrezeptoren. Phy-logenetisch besteht zwischen den H1-Rezeptoren und denmuskarinischen Acetylcholinrezeptoren eine engere Ver-wandtschaft als zwischen den H1- und H2-Rezeptoren [5].So ist es nicht verwunderlich, dass H1-Antihistaminika derersten Generation häufig Atropin-artige Nebenwirkungenauslösen.

Bestimmten H1-Antihistaminika wird eine Mastzell-stabi-lisierende Wirkung zugeschrieben. Für eine klinische Rele-vanz müsste belegt werden, dass diese Wirkung in therapeu-tisch erreichbaren Konzentrationen vorkommt und dass dieSubstanz anderen, nicht-mastzellstabilisierenden H1-Antihis-taminika überlegen ist.

Einige H1-Antihistaminika können bestimmte kardialeK+-Kanäle blockieren, die für die Repolarisationsphase desAktionspotenzials wichtig sind. Dadurch kann das QT-In-tervall verlängert und eine Herzrhythmusstörung ausgelöstwerden. Im Hinblick auf die Wirkort-Selektivität ist inte-ressant, dass das K+-Kanal-blockierende Agens im Falle von

Terfenadin ein „Prodrug“ ist, das nachBiotransformation zu Fexofenadin dieAffinität zu H1-Rezeptoren behält [6],aber die K+-Kanal-blockierende Wirk-samkeit verliert. Das antihistaminischeWirkbild nach peroraler Gabe von Ter-fenadin wird wegen einer raschen„First-pass“-Biotransformation durchden Metaboliten Fexofenadin geprägt– es sei denn, die hepatische Bio-transformation wäre behindert.

ZNS-GängigkeitAls Unterscheidungsmerkmal zwischenden H1-Antihistaminika der ersten undder zweiten Generation gilt die Fähig-keit, eine Sedierung herbeizuführen.Die sedierende Wirkung lässt sich aufeine Blockade der zentralen H1-Re-zeptoren zurückführen, die Wachheitvermitteln. Die nicht oder wenig se-dierenden Antihistaminika der 2. Ge-

neration vermögen die Blut-Hirn-Schranke nur schwer zuüberwinden. Sie sind daher weniger sedierend. Die gerin-gere ZNS-Gängigkeit dieser Substanzen ist durch physiko-chemische Eigenschaften der Substanzen nicht befriedigenderklärbar. Sie erscheinen nicht auffällig weniger lipophil alsdie Antihistaminika der ersten Generation und sie sind nichtpermanent geladen wie beispielsweise das nicht ZNS-gän-gige quartäre Atropin-Derivat Ipratropium. Seit kurzem lie-gen Befunde vor, die darauf hindeuten, dass Antihistamini-

H1: Juckreiz, Bronchokonstriktion, Darmperistaltik

H4: Chemotaxis von Leukozyten, z.B. von Eosinophilen

Vasodilatation

glatte Muskelzellen

NOH2

H1 Endothel H1

Endothelzell-Kontraktion

Quaddeln, Ödem

A B B . 3 | H I S TA M I N U N D E R S C H E I N U N G E N D E R ATO PI E

Die Gefäßerweiterung in den Arteriolen kann über H1- und über H2-Rezeptoren ausgelöst werden: H1-Rezeptoren in der Zellmembran der Gefäßendothelzellen induzieren die Abgabe von Stickstoffmonoxid,das die glatten Gefäßmuskelzellen der Arteriolen erschlaffen lässt; durch Erregung von H2-Rezeptoren der Gefäßmuskelzellen kann der Gefäßtonus vermindert werden. In den Venolen vermitteln H1-Rezeptorenein Zusammenziehen der Endothelzellen; die entstehenden Lücken erlauben den Ausstrom von Plasma-flüssigkeit.

Endothelzelle

P-Glykoprotein

Desloratadin

Astrozyten-Endfüßchen

Basal-membran

tight junctionHN

N

Cl

ABB. 4 | BLUT-HIRN-SCHRANKE UND ARZNEISTOFFPUMPE

Das P-Glykoprotein ist in den Endothelzellen der Hirnkapilla-ren an der blutseitigen Zellmembran vorhanden und pumptin die Endothelzelle eingedrungene Wirkstoffmoleküle in dasBlut zurück. Da die Pumpe sättigbar ist, können auch Anti-histaminika der 2. Generation bei höherer Dosierung einensedierenden Effekt entfalten.

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ka der zweiten Generation Substrate einer Arzneistoffpum-pe vom Typ des P-Glykoprotein sein können (Abb. 4). AnKnock-out-Mäusen, bei denen mittels gentechnischer Me-thodik das Gen für das P-Glykoprotein ausgeschaltet wor-den war, fluteten Substanzen wie Cetirizin, Loratadin undDesloratadin stärker im ZNS an als bei normalen Mäusen.Antihistaminika der ersten Generation (z.B. Diphenhydra-min und Hydroxyzin) hingegen traten bei den Knock-out-Mäusen in gleichem Ausmaß wie bei normalen Mäusen indas Gehirn über [7]. Das P-Glykoprotein ist in den Endo-thelzellen der Hirnkapillaren an der blutseitigen Zellmem-bran vorhanden und pumpt in die Endothelzelle einge-drungene Wirkstoffmoleküle in das Blut zurück. Die Pum-pe ist sättigbar. Dies würde erklären, weshalb Antihista-minika der zweiten Generation bei höherer Dosierung, wel-che die Pumpe überfordert, durchaus einen sedierendenEffekt entfalten können.

Die Struktur-Wirkungs-Beziehungen von Arzneistoffenfür die Transportierbarkeit durch das P-Glykoprotein liegennoch weitgehend im Dunkeln. So gesehen ist es nicht ver-wunderlich, dass sich strukturell scheinbar nah verwandteH1-Antihistaminika in ihrer ZNS-Gängigkeit voneinanderunterscheiden können. Einige Substanzen, die der zweitenGeneration zugerechnet werden, leiten sich direkt vonArzneistoffen der ersten Generation ab. So ist die chemischeVerwandtschaft zwischen Cetirizin und Ebastin auf der ei-nen Seite und den älteren Antihistaminika Hydroxyzin undDiphenylpyralin auf der anderen Seite deutlich zu erkennen(Abb. 5).

Die Strukturabhängigkeit der Transportierbarkeit durchdie endotheliale Arzneistoff-Pumpe würde auch erklären,weshalb sich die sedierende Potenz der H1-Anthistaminikader zweiten Generation unterscheidet.

Nebenwirkungen bei systemischer AnwendungH1-Antihistaminika der 1. Generation

Die sedierende Wirkung kann unerwünscht sein oder thera-peutisch nützlich, z.B. bei quälendem Juckreiz. Folgen derBlockade von muskarinischen Acetylcholinrezeptoren kön-nen sein Mundtrockenheit, Obstipation, Miktionsstörungenbei Prostataadenom, Augeninnendrucksteigerung bei Eng-winkelglaukom sowie Agitiertheit und Verwirrung vor allembei Kindern und Älteren. Eine Scopolamin-artige, antimus-karinische Wirkung kann zum gewünschten Effekt bei Kinetosen beitragen. Cyproheptadin und Pizotifen sind trizyklische Substanzen mit Affinität zu Histamin- und zuSerotoninrezeptoren; sie verursachen eine Appetitsteige-rung, die therapeutisch ausgenutzt wird.

H1-Antihistaminika der 2. GenerationBei diesen Substanzen fehlen antimuskarinische Effekteweitgehend. Die Fähigkeit, das QT-Intervall zu verlängernund damit lebensbedrohliche Herzarrhythmien vom Typder Torsades de pointes zu verursachen, ist wohl das Haupt-problem bei einigen Vertretern dieser Gruppe. Astemizol

(Hismanal) wurde aufgrund dieser Nebenwirkung vomMarkt genommen. Diese Substanz sowie Emedastin und Mi-zolastin werden zu den Benzimidazolen gezählt. Das eben-falls potenziell kardiotoxische Emedastin wird nur topischam Auge angewandt. Mizolastin ist bei Patienten mit vor-bestehender QT-Verlängerung oder Störungen des Elektro-lythaushaltes, insbesondere Hypokaliämie, kontraindiziert.Diese Hinweise gelten auch für Ebastin, das vom Diphe-nylpyralin (1. Generation) abgeleitet ist. Wegen der poten-ziellen Kardiotoxizität wurde Terfenadin der Verschrei-bungspflicht unterstellt, während sein aktiver MetabolitFexofenadin offenbar auch in höherer Dosierung keine QT-Verlängerung verursacht [8].

Abkömmlinge von Substanzen der zweiten Generationwie Fexofenadin, deren proarrhythmische Eigenschaftenzurückgedrängt sind, werden zuweilen auch als Antihista-minika der dritten Generation bezeichnet [9, 10].Wir möch-ten uns auf die in den meisten Fällen praktizierte Eintei-lung in zwei Generationen beschränken.

Es ist nicht so, dass die Antihistaminika der ersten Ge-neration keinerlei kardiotoxisches Potenzial besäßen. Sowerden für Hydroxyzin, Diphenhydramin, Promethazin undPheniramin Herzrhythmusstörungen unterschiedlicher Artbeschrieben [11, 12].

Innerhalb der Gruppe der Antihistaminika der zweitenGeneration gibt es graduelle Unterschiede hinsichtlich derSedierungspotenz. In einer Postmarketing-Beobachtungs-studie [12] wurden die sedativen Eigenschaften von vierAntihistaminika quantifiziert. Für Loratadin wurde hierbeider Risiko-Faktor (odds ratio) für Sedierung willkürlich auf1,0 gesetzt. Für Fexofenadin fand sich ein Risiko-Faktor von0,63, für Acrivastin einer von 2,79 (in den USA erhältlich)und für Cetirizin einer von 3,53. Viele Bundesstaaten derUSA haben Gesetze verabschiedet, in denen definiert ist, in

NN

O

HO

N

O

CH3

N

O O

CH3

CH3

CH3

NN

O

HO O

Cl

Diphenylpyralin Hydroxyzin

Ebastin Cetirizin

1. Generation

2. Generation

Cl

ABB. 5 | STRUKTURVERWANDTSCHAFTEN ZWISCHEN H1-ANTIHISTAMINIKA

Einige H1-Antihistaminika, die der zweiten Generation hinzugerechnet werden, leiten sich direkt von Arzneistoffen der ersten Generation ab.

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welchen Fällen eine Verkehrstüchtigkeit nicht gewähr-leistet ist. Die Einnahme von Antihistaminika der ersten Ge-neration und von Cetirizin zum Beispiel wäre ein solcherFall. Eine sehr geringe Sedierungspotenz haben Loratadinund Fexofenadin. Piloten wurde die Einnahme beider Sub-stanzen von der US Federal Aviation Administration ge-nehmigt [12]. Andererseits wurden Cetirizin, Loratadin undDesloratadin von der FDA (Food and Drug Administrati-on) als Substanzen charakterisiert, die müde machen kön-nen, vor allem wenn sie in einer höheren als der empfoh-lenen Dosierung eingesetzt werden. Alle Fachinformationender neueren Antihistaminika weisen auf eine Sedierung inEinzelfällen hin und verweisen auf eine Wechselwirkungmit Alkohol und zentral sedierenden Substanzen. Es darfdabei allerdings nicht vergessen werden, dass das allergi-sche Geschehen selbst Ermüdungserscheinungen bewirkenkann [13].

Nebenwirkungen bei lokaler AnwendungDurch die lokale Anwendung lassen sich unerwünschte sys-temische Begleitwirkungen niedrig halten. Entsprechendihrer kationischen amphiphilen Natur können H1-Antihi-staminika der ersten Generation in ausreichender Konzen-tration lokalanästhetisch wirken. Diphenhydramin wird alsInhaltsstoff eines Kathetergels (Cathejell) eingesetzt. Dielokalanästhetische Wirkung mag zur Wirkung von Substan-zen wie Bamipin, Chlorphenoxamin, Clemastin und Dime-tinden bei juckenden Hauterscheinungen beitragen. DieMöglichkeit der Allergisierung durch lokal angewandte Antihistaminika sollte bedacht werden.

EliminationEinige Antihistaminika werden überwiegend unverändertrenal eliminiert, andere unterliegen einer hepatischen Bio-transformation. Je nach Wirkstoff ist bei der Dosierung aufLeber- und Nierenfunktionsstörungen zu achten.

WechselwirkungenInteraktionen ist ein spezieller Beitrag in diesem Heft ge-widmet (vgl. Beitrag: E. Haen „Arzneimittelwechselwir-kungen mit H1-Antihistaminika“, S. 106). Hier sei nur an-gesprochen, dass in den meisten Fachinformationen auf dieverstärkte Sedierung durch H1-Antihistaminika beider Gene-rationen in Kombination mit Alkohol und Psychopharmakahingewiesen wird. Der Hinweis auf diese Wechselwirkungsollte beim Beratungsgespräch mit dem Kunden in der Apotheke nicht fehlen.

Anwendung in Schwangerschaft und StillzeitEs gibt keine Hinweise auf teratogene Wirkungen. Im Tier-versuch sind embryotoxische Effekte unter hoher Do-sierung beobachtet worden. Einige Hersteller raten von derAnwendung während der Schwangerschaft ab. Einige Anti-histaminika können in signifikanter Menge in die Mutter-milch übergehen. Hersteller bestimmter Antihistaminika raten daher vom Gebrauch in der Stillzeit ab.

Anwendungen von H1-AntihistaminikaEs sei angemerkt, dass fast alle Antihistaminika der erstenGeneration in Deutschland bislang lediglich registriert sindund der Nachzulassung durch das BfArM bedürfen.

AntiallergikaH1-Antihistaminika sind wirksam bei allergischer Rhinokon-junktivitis. Bei der allergischen Rhinitis betrifft dies dieSymptome Niesreiz und Sekretion, aber kaum die „ver-stopfte Nase“. Bei Rhinitis im Rahmen einer Erkältungs-krankheit bieten sie keinen Nutzen. Bei atopischem Ekzemkönnen Antihistaminika den Juckreiz günstig beeinflussen,wohl auch wegen des sedierenden Effektes. Im Stufensche-ma der Asthma-Therapie [14] sind H1-Antihistaminika nichtenthalten. Sie können einen Nutzen haben, wenn beimAsthmatiker gleichzeitig eine allergische Rhinitis besteht.

AntiemetikaH1-Antihistaminika der ersten Generation wie Meclozin undDimenhydrinat (Diphenhydramin plus 8-Chlortheophyllin)werden bei Übelkeit und Erbrechen unterschiedlicher Ge-nese (Reisekrankheit, Erbrechen bei Migräne, vestibulärenStörungen) angewendet. Zur Wirkung mag der antihista-minische wie auch der antimuskarinische, Scopolamin-ar-tige Effekt beitragen. Bei Kindern ist die Dosierung wegender Gefahr „paradoxer“ zentraler Erregung streng einzu-halten.

Sedativa und SchlafmittelDie rezeptfreien H1-Antihistaminika der ersten Generationkönnen bei gelegentlichen Schlafstörungen nützlich sein. Ihre hypnotische Potenz ist gering, anticholinerge Neben-wirkungen sind zu berücksichtigen, bei Dauergebrauchkann die hypnotische Wirksamkeit schwinden.

SchlussbemerkungAuf dem Gebiet der H1-Antihistaminika gibt es eine Fülle vonArzneistoffen mit unterschiedlichem Wirkprofil. Ebenso wiebei den H2-Antihistaminika scheint wenig Raum für weitereechte Innovationen zu bestehen. Gespannt darf man sein, obes gelingt, Arzneistoffe zur Beeinflussung von H3- und von H4-Rezeptoren zu entwickeln.

Zitierte Literatur[1] Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young

JM, Schunack W, Levi R, and Haas HL (1997) International Union ofPharmacology. XIII. Classification of Histamine Receptors. PharmacolRev 49:253-278.

[2] Nguyen T, Shapiro DA, George SR, Setola V, Lee DK, Cheng R, RauserL, Lee SP, Lynch KR, Roth BL, and O'Dowd BF (2001) Discovery of aNovel Member of the Histamine Receptor Family. Mol Pharmacol59:427-433.

[3] Hough LB (2001) Genomics Meets Histamine Receptors: New Sub-types, New Receptors. Mol Pharmacol 59:415-419.

[4] Jablonowski JA, Grice CA, Chai W, Dvorak CA, Venable JD, Kwok AK,Ly KS, Wei J, Baker SM, Desai PJ, Jiang W, Wilson SJ, Thurmond RL,Karlsson L, Edwards JP, Lovenberg TW, and Carruthers NI (2003) The First Potent and Selective Non-Imidazole Human Histamine H4Receptor Antagonists. J Med Chem 46:3957-3960.

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[5] Vernier P, Cardinaud B, Valdenaire O, Philippe H, and Vincent JD(1995) An Evolutionary View of Drug-Receptor Interaction: the Bio-amine Receptor Family. Trends Pharmacol Sci 16:375-381.

[6] Gillard M, Van der PC, Massingham R, and Chatelain P (2002) Bin-ding Characteristics of [3H]Levocetirizine to Cloned Human H1-Histamine-Receptors Expressed in CHO Cells. Inflamm Res 51 Suppl1:S77-S78.

[7] Chen C, Hanson E, Watson JW, and Lee JS (2003) P-Glycoprotein Li-mits the Brain Penetration of Nonsedating but Not Sedating H1-An-tagonists. Drug Metab Dispos 31:312-318.

[8] Simons FE (2002) Comparative Pharmacology of H1 Antihistamines:Clinical Relevance. Am J Med 113 Suppl 9A:38S-46S.

[9] Handley DA and Graff F (1998) A Look Ahead. Third-Generation Antihistamines. Adv Nurse Pract 6:53-4, 72.

[10] Holgate ST (2002) Considerations on Third Generation Antihistami-nes. Clin Exp Allergy 32:179.

[11] Taglialatela M, Timmerman H, and Annunziato L (2000) CardiotoxicPotential and CNS Effects of First-Generation Antihistamines. TrendsPharmacol Sci 21:52-56.

[12] Casale TB, Blaiss MS, Gelfand E, Gilmore T, Harvey PD, Hindmarch I,Simons FE, Spangler DL, Szefler SJ, Terndrup TE, Waldman SA, Wei-ler J, and Wong DF (2003) First Do No Harm: Managing Antihistami-ne Impairment in Patients With Allergic Rhinitis. J Allergy Clin Im-munol 111:S835-S842.

[13] Slater JW, Zechnich AD, and Haxby DG (1999) Second-GenerationAntihistamines: a Comparative Review. Drugs 57:31-47.

[14] Global Initiative for Asthma: Global Strategy for Asthma Manage-ment and Prevention (2002), NIH Publication No 02-3659;www.ginasthma.com

Die AutorenDr. rer. nat. Andreas Dittmann (geb. 1967); Pharma-ziestudium an der Universität Bonn; 1992 Approba-tion als Apotheker; 1993 Mitarbeiter einer öffent-lichen Apotheke; 1993-1998 Aufbau und Leitung einer Berufsschule in Paraná, Brasilien; 1998 Öffent-lichkeitsarbeit beim ICW e.V., Bornheim; 1999-2002Weiterbildung zum Fachapotheker für Arzneimittel-information; 1999-2003 Promotion unter der Lei-tung von Prof. Dr. K. Mohr.

Prof. Dr. med. Klaus Mohr (geb. 1953); Medizinstu-dium an der Universität Kiel; 1978 Approbation alsArzt; 1979-1980 Geschwaderarzt bei der Bundes-marine; 1980 Promotion bei Prof. Dr. Heinz Lüll-mann; 1986 Facharztanerkennung Pharmakologieund Toxikologie; 1988 Habilitation; seit 1992 Leiterdes Bereichs Pharmakologie und Toxikologie imPharmazeutischen Institut der Universität Bonn; seit2001 Sprecher des Graduiertenkollegs „Struktur undmolekulare Interaktion als Basis der Arzneimittel-wirkung“; seit 2002 Prodekan für Lehre und Studiumder Mathematisch-naturwissenschaftlichen Fakultätder Universität Bonn; seit 2003 Generalsekretär derDPhG.

AnschriftDr. Andreas Dittmann, Prof. Dr. Klaus MohrPharmakologie und ToxikologiePharmazeutisches Institut Universität BonnGerhard-Domagk-Str. 3 53121 Bonne-mail: k.mohr@uni-bonn.de

Z U R T I T E L S E I T E : |Das Titelbild zeigt Pollenkörner von Matricaria recutita, Arnica montana, Lavandula an-gustifolia, Tilia cordata und Calendula officinalis.

Die Pollenkörner der meisten Blütenpflanzen sind relativ groß und schwer und werdenvon Insekten von Blüte zu Blüte transportiert. Viele Bäume, Sträucher und Gräser produ-zieren dagegen oft sehr viele und feinere Pollen, die vom Wind verbreitet werden undaufgrund ihrer geringen Größe tief in die Atemwege eindringen können. Durch den Kon-takt mit den Fremdproteinen kann es dann zu einer Überreaktion des Immunsystemskommen. Es ist somit nicht verwunderlich, dass Pollen die häufigsten IInnhhaallaattiioonnssaalllleerr--ggeennee sind (Abb. 1).

Nicht selten folgt einer Pollenallergie eine so genannte pollenassoziierte Nahrungsmit-telallergie die durch eine Strukturverwandtschaft der Pollenallergene mit den NNaahh--rruunnggssmmiitttteellaalllleerrggeenneenn (= IInnggeessttiioonnssaalllleerrggeennee) bedingt wird.

So reagieren Patienten mit Baumpollenallergien, also beispielsweise Allergien gegen Birkenpollen, oft auf grüne Äpfel, Wal-, Hasel- oder Erdnüsse. Bei Patienten mit Gräserallergien sind Reaktionen auf Hülsenfrüchte, Getreidekörnern, Tomaten oder Melonen typisch. Kräuterpollenallergiker entwickeln oft Symptome nach dem Genussvon rohem Gemüse wie Sellerie oder Gewürzen wie Curry, Paprika, Kümmel oder Pfeffer.

Den beiden genannten Allergentypen sind die KKoonnttaakkttaalllleerrggeennee, die durch Hautkontaktaufgenommen werden, wie z.B. Nickel und die IInnjjeekkttiioonnssaalllleerrggeennee, die in den Körpereingespritzt werden, wie z.B. Insektengifte, aber auch Medikamente oder Röntgenkon-trastmittel gegenüberzustellen.

Betrachtet man sich die allergenen Proteine, so sind ein paar Gemeinsamkeiten festzustellen:

• Molekulargewichte zwischen 10 und 70 kDa,

• Strukturmerkmale, die die Induktion von IgE-Antikörpern auslösen können,

• Resorbierbarkeit im Magen-Darmtrakt oder über die Schleimhäute der Atemwege,

• Resistenz gegen verdauende Enzyme; häufig selbst proteolytisch aktiv

• relative Beständigkeit der allergenen Eigenschaften gegenüber Hitze- und Säurebe-handlung

• relativ hoher prozentualer Anteil

Pollen

Milben

Tier-epithelien

Schimmel-pilze

Sonstige

A B B . 1 Unter den Inhala-tionsallergenen sind Pollenam häufigsten für eine Über-empfindlichkeit verantwort-lich. Mit deutlichem Abstandfolgen Milben, Tierepithelienund Schimmelpilze.

106 | Pharm. Unserer Zeit | 33. Jahrgang 2004 | Nr. 2 DOI:10.1002/pauz.200400060 © 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Worauf sollte bei der Abgabe von Antihistaminika geachtetwerden?

Arzneimittelwechselwirkungenmit H1-AntihistaminikaEKKEHARD HAEN

Pharmakodynamische InteraktionenH1-Antihistaminika werden als Schlafmittel, als Antiemetikaund zur Behandlung von Typ-I-Allergien (IgE vermittelte Al-lergien) angewendet. Für den Apotheker ist die Verschrei-bung als Antiallergikum Anlass, sich bei der Abgabe weite-rer Arzneimittel Gedanken über Arzneimittelrisiken zu ma-chen. Typ-I-Allergiker haben ein erhöhtes Risiko, unterβ-Blockern einen Asthmaanfall zu entwickeln. Auch aufACE-Hemmer können die Atemwege von Al-lergikern empfindlicher reagieren,hier kann sich der Betroffenerichtiggehend in eine Atem-not “hineinhusten”.

Einige H1-Antihista-minika sind chemischmit den trizyklischenPhenothiazin-Neuro-leptika verwandt.Psychopharmaka in-teragieren mit einerVielzahl verschiede-ner Rezeptoren imBereich des Zentralner-vensystems, viele antago-nisieren H1-Rezeptoren undMuskarinrezeptoren (M1-An-tagonisten). Als Mechanismus fürdie Interaktion zwischen H1-Antihistami-

Unter Arzneimittelwechselwirkungen versteht man Interak-tionen zwischen verschiedenen, gleichzeitig applizierten Arzneistoffen. Einige der für die Praxis relevantesten Interak-tionen bei der Anwendung von Arzneimitteln treten fernerzwischen Arznei- und Lebensmitteln (z.B. Grapefruitsaft) undzwischen Arznei- und Genussmitteln wie Alkohol und Tabak-rauch auf. Im Folgenden werden relevante Wechselwirkungenmit H1-Antihistaminika beschrieben.

nika und Psychopharmaka kann daher die additive Wirkungan H1- und M1-Rezeptoren angesehen werden [gleichsinni-ge Wirkung (Antagonismus) auf Rezeptorebene].

Die für pharmakodynamische Interaktionen kritischeWirkung der H1-Antihistaminika ist die Sedierung. ÄltereH1-Antihistaminika sind stärker sedierend als die neuerenWirkstoffe, da letztere weniger gut die Blut-Hirn-Schrankeüberwinden. Die Sedierung wird durch andere zentral sedie-rend wirksame Substanzen, wie z.B. Benzodiazepine, sedie-rende (niederpotente) Neuroleptika, sedierende Antidepres-siva, Opioide, zentral Blutdruck senkende Wirkstoffe wieClonidin und Moxonidin, additiv verstärkt. Besonders kri-tisch ist in dieser Hinsicht der gleichzeitige Alkoholgenusszu sehen (Interaktion gleicher Wirkungen).

Daneben kommt es auch zur Verstärkung anticholiner-ger Wirkungen bei der Kombination von H1-Antihistamini-ka (insbesondere solchen vom Phenothiazin-Typ wie Pro-methazin) mit Neuroleptika und trizyklischen Antidepres-siva. Blutdrucksteigerungen, Tachykardie, Obstipation,Harnverhalt und Glaukom sind die Folge. Eine langanhal-tende anticholinerg verursachte Mundtrockenheit kann Ka-

ries und Zahnausfall fördern.H1-Antihistaminika wirken in hohen

Konzentrationen auf Kalium-kanäle, die am Herzen für ei-

ne ordnungsgemäße Erre-gungsrückbildung ver-

antwortlich sind. Dieslässt sich im EKG aneiner Verlängerungder QT-Strecke, alsoder Zeit zwischendem Beginn der Q-Zacke und dem Ende

der T-Welle (Abb. 1),ablesen. Steigt diese

Zeit frequenzkorrigiert(QTc-Zeit) bei Männern

über 430 ms, bei Frauen aufüber 450 ms, so ist mit dem Auf-

treten schwerer Herzrhythmusstörungen

Kontraindikation

Wechselwirkung

Arzneistoff

Krankheit

Arzneistoff

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wie Torsades de pointes zu rechnen, das in Kammerflim-mern übergehen und den Tod des Patienten zur Folge ha-ben kann. Es gibt eine ganze Reihe weiterer Substanzen mitähnlichen Wirkungen auf die QTc-Zeit, deren Wirkungensich potenziell additiv verstärken können (Agonismus aufRezeptorebene). Hierzu gehören einige Neuroleptika, Anti-depressiva vom Typ der trizyklischen Verbindungen, mo-tilitätsfördernde Substanzen im Magen-Darm-Trakt wie Ci-saprid, Antiarrhythmika der Klasse I u.a. (aktuelle Liste imInternet unter: www.torsades.org).

Pharmakokinetische InteraktionenInteraktionen bei der Aufnahme in den Körper und bei derVerteilung im Körper treten bei H1-Antihistaminika nur beieinzelnen Substanzen auf.

Hingegen kommt es zu praktisch relevanten Interaktio-nen bei der Elimination von Antihistaminika. Terfenadinwird sehr schnell über das Cytochrom-P450-IsoenzymCYP3A4/5 verstoffwechselt, wobei aber ein nach wie voraktiver Metabolit gebildet wird. Xenobiotika, die dieses En-zymsystem hemmen, z.B. Makrolid-Antibiotika (u.a. Ery-thromycin), Gyrasehemmer (u.a. Ciprofloxacin), Protonen-pumpenhemmer (u.a. Omeprazol), H2-Antihistaminika (u.a.Cimetidin), Azol-Antimykotika (u.a. Ketoconazol), blockie-ren den Abbau von Terfenadin und erhöhen so die Wirk-stoffkonzentration. Auch die in dem Lebensmittel Grape-fruitsaft enthaltenen Flavonoide haben den gleichen Effekt.Durch Blockade von CYP3A4/5 in der Darmwand steigt beiregelmäßigem Trinken von Grapefruitsaft die Bioverfüg-barkeit von Terfenadin um das 4-6fache. Im Falle des Ter-fenadins hat dies zur Marktrücknahme der hohen Dosie-rungen > 60 mg geführt, da in Kombination mit dem Mak-rolid-Antibiotikum Erythromycin und mit Grapefruitsaftschwere Herzrhythmusstörungen aufgetreten sind. Astemi-zol ist aus dem gleichen Grund ganz vom Markt ver-schwunden. Der aktive Metabolit des Terfenadins ist heuteunter der Bezeichnung Fexofenadin auf dem Markt.

Monoaminooxidase-Hemmstoffe und erhöhte Proges-teronkonzentrationen in der Schwangerschaft und bei Ein-nahme oraler Kontrazeptiva hemmen ebenfalls den oxida-tiven Stoffwechsel in der Leber. Hierdurch kommt es zu einer Konzentrationserhöhung aller beteiligten Wirkstoffeim Körper mit der Folge der Verstärkung ihrer Wirkungen:Blutdruckerhöhungen der MAO-Hemmer, Sedierung der H1-Antihistaminika.

H1-Antihistaminika können ihren Stoffwechsel aberauch selbst induzieren: So lässt die Wirkung von Diphen-hydramin bei länger dauernder Anwendung von selbst nach(Toleranzentwicklung), in Komedikation werden aber auchdie Wirkungen von Glucocorticoiden, Phenobarbital,Phenytoin, Antikoagulantien und Phenylbutazon verringert.

ZusammenfassungH1-Antihistaminika sind im allgemeinen gut verträglicheSubstanzen, die auch nur zu wenigen Arzneimittelinter-aktionen Anlass geben. Am relevantesten sind die pharma-kodynamische Verstärkung der sedierenden Wirkung ande-rer ZNS-aktiver Substanzen und der pharmakokinetisch be-dingte Anstieg der Wirkstoffkonzentration bei Hemmung desCytochrom-P450-Enzymsystems durch Arznei- und Lebens-mittel mit der Folge potenziell lebensbedrohlicher Herz-rhythmusstörungen. Werden H1-Antihistaminika zur Be-handlung von Allergien eingenommen, so sollten β-Blockernur mit großer Vorsicht angewendet werden.

Der Autor

AnschriftProf. Dr. med. Dr. rer. nat. Ekkehard HaenKlinische PharmakologieKlinik und Poliklinik für Psychiatrie und Psychotherapieder Universität im Bezirksklinikum RegensburgUniversitätsstr. 8493053 Regensburge-mail: ekkehard.haen@klinik.uni-regensburg.de

+0–

UP

T

SQ

R

PQ-Intervall0,12-0,20 sec

QT-Intervall

QU-Intervall

S ≥

0,0

8 se

c

R 0,6-2,6 mV

Q ≤

0,0

3 se

c <

1/4

von

R

A B B . 1 | D I E Q T- Z E I T I M E KG